JP2013532184A - N-sulfonylbenzamide derivatives useful as voltage-gated sodium channel inhibitors - Google Patents

Abstract

またはその薬学的に許容される塩に関し、式中、Ｈｅｔ^１、Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、本明細書に定義されているとおりである。Ｎａｖ１．７阻害剤は、広範囲の障害、特に疼痛の治療に潜在的に有用である。
【選択図】なしThe present invention relates to sulfonamide derivatives, their use in medicine, compositions containing them, methods for their preparation and intermediates used in such methods. More particularly, the present invention relates to novel sulfonamide Nav1.7 inhibitors of formula (I):

Or with respect to a pharmaceutically acceptable salt thereof, wherein Het ¹ , X, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined herein. Nav1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain.
[Selection figure] None

Description

  The present invention relates to sulfonamide derivatives, their use in medicine, compositions containing them, methods for their preparation and intermediates used in such methods.

  Voltage-gated sodium channels are present in all excitable cells, including muscle myocytes and neurons in the central and peripheral nervous system. In neurons, sodium channels are primarily responsible for causing a rapid rise in action potential. Thus, sodium channels are essential for the initiation and propagation of electrical signals in the nervous system. Therefore, the proper function of sodium channels is necessary for the normal function of nerve cells. Therefore, abnormal sodium channel function is associated with epilepsy (Yogeeswari et al., Curr. Drug Targets, 5 (7): 589-602 (2004)), arrhythmia (Noble D., Proc. Natl. Acad. Sci. USA, 99 (9): 5755-6 (2002)), myotonia (Cannon, SC, Kidney Int. 57 (3): 772-9 (2000)), and pain (Wood, JN et al., J. Neurobiol , 61 (1): 55-71 (2004)) (for a general review of genetic ion channel disorders, see Hubner CA, Jentsch TJ, Hum. Mol. Genet., 11 (20): 2435-45 (2002)).

  At present, there are at least nine known members of the voltage-gated sodium channel (VGSC) α subunit family. The names of this family include SCNx, SCNAx and Navx. x. The VGSC family is systematically divided into two subfamilies, namely Nav1. x (all except SCN6A) and Nav2. x (SCN6A). Nav1. The x subfamily is functionally divided into two groups: those that are sensitive to blockade by tetrodotoxin (TTX-sensitive or TTX-s) and those that are resistant to blockade by tetrodotoxin (TTX-resistant or TTX-). r) can be subdivided.

  Nav1.7 (PN1, SCN9A) VGSC is sensitive to blockade by tetrodotoxin and is preferentially expressed in peripheral sympathetic and sensory neurons. The SCN9A gene has been cloned from multiple species such as human, rat and rabbit and shows about 90% amino acid identity between human and rat genes (Toledo-Aral et al., Proc. Natl. Acad. Sci. USA, 94 (4): 1527-1532 (1997)).

  A growing body of evidence suggests that Nav1.7 may play an important role in various pain conditions such as acute, inflammatory and / or neuropathic pain. Deletion of the SCN9A gene in mouse nociceptive neurons reduced mechanical and thermal pain thresholds and reduced or eliminated inflammatory pain responses (Nassar et al., Proc Natl Acad Sci USA, 101 (34) : 12706-11 (2004)). In humans, the Nav1.7 protein has been shown to accumulate in neuromas, particularly painful neuromas (Kretschmer et al., Acta. Neurochir. (Wien), 144 (8): 803-10 (2002). ). Both familial and sporadic Nav1.7 gain-of-function mutations are associated with first-order limb pain (Yang et al., J. Med. Genet.), A disease characterized by limb burning and inflammation. , 41 (3): 171-4 (2004)) and severe pain disorder (Waxman, SG Neurology. 7; 69 (6): 505-7 (2007)). The non-selective sodium channel blockers lidocaine and mexiletine can provide symptomatic relief in cases of familial limb pain (Legroux-Crepel et al., Ann. Dermatol Venereol., 130: 429-433). The reports that carbamazepine is effective in reducing the number and severity of seizures in PEPD (Fertleman et al, Neuron .; 52 (5): 767-74 (2006)) are consistent with this observation. Yes. Further evidence for the role of Nav1.7 in pain is found in the phenotype of loss-of-function mutations in the SCN9A gene. Cox and colleagues (Nature, 444 (7121): 894-8 (2006)) found an unusual autosomal recessive disorder characterized by loss-of-function mutations in SNC9A and complete insensitive or insensitivity to painful stimuli. We first reported an association with congenital analgesia (CIP). Subsequent investigations have revealed several different mutations that cause loss of function of the SCN9A gene and the CIP phenotype (Goldberg et al, Clin Genet .; 71 (4): 311-9 (2007), Ahmad et al , Hum Mol Genet. 1; 16 (17): 2114-21 (2007)).

  Thus, Nav1.7 inhibitors are used in a wide range of disorders, particularly pain, such as acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain (such as postoperative pain), viscera, It is potentially useful in the treatment of mixed pain types (such as cancer pain, back pain and orofacial pain) involving the digestive tract, skull tissue, musculoskeletal system, spine, genitourinary system, cardiovascular system and CNS.

  Certain inhibitors of voltage-gated sodium channels useful in the treatment of pain are known. Thus, WO 2005/014914 discloses heteroarylaminosulfonylphenyl derivatives, WO 2008/118758 discloses arylsulfonamides, and WO 2009/012242 N-thiazolylbenzenesulfonamide is disclosed.

However, there is still a need to provide novel Nav1.7 inhibitors that are good drug candidates.
Preferably, the compound is a selective Nav1.7 channel inhibitor. That is, preferred compounds exhibit a higher affinity for the Nav1.7 channel than other Nav channels. In particular, they must exhibit an affinity for the Nav1.7 channel that is higher than their affinity for the Nav1.5 channel. Advantageously, the compound is one that exhibits little or no affinity for the Nav1.5 channel.

  Selectivity for a Nav1.7 channel higher than Nav1.5 may improve one or more of the side effect profiles. Without wishing to be bound by theory, such selectivity is believed to reduce any cardiovascular side effects that may be associated with affinity for the Nav1.5 channel. The compounds are 10-fold, more preferably 30-fold, most preferably the Nav1.7 channel when compared to their selectivity for the Nav1.5 channel while maintaining good potency for the Nav1.7 channel. It is preferable that the selectivity is 100 times.

  Furthermore, preferred compounds are well absorbed in the gastrointestinal tract, are metabolically stable, in particular have a good metabolic profile for the toxicity or allergenicity of any metabolites formed, or the Nav1.7 channel It must have one or more of the properties of having favorable pharmacokinetic properties while still retaining their active properties as inhibitors. They must be non-toxic and show few side effects. The ideal drug candidate must be stable, non-hygroscopic and exist in a physical form that is easily formulated.

  The inventors have discovered a novel sulfonamide Nav1.7 inhibitor.

International Publication No. 2005/013914 International Publication No. 2008/118758 International Publication No. 2009/012242

Yogeeswari et al., Curr. Drug Targets, 5 (7): 589-602 (2004) Noble D., Proc. Natl. Acad. Sci. USA, 99 (9): 5755-6 (2002) Cannon, SC, Kidney Int. 57 (3): 772-9 (2000) Wood, JN et al., J. Neurobiol., 61 (1): 55-71 (2004) Hubner CA, Jentsch TJ, Hum. Mol. Genet., 11 (20): 2435-45 (2002) Toledo-Aral et al., Proc. Natl. Acad. Sci. USA, 94 (4): 1527-1532 (1997) Nassar et al., Proc Natl Acad Sci USA, 101 (34): 12706-11 (2004) Kretschmer et al., Acta. Neurochir. (Wien), 144 (8): 803-10 (2002) Yang et al., J. Med. Genet., 41 (3): 171-4 (2004) Waxman, SG Neurology. 7; 69 (6): 505-7 (2007) Legroux-Crepel et al., Ann. Dermatol Venereol., 130: 429-433 Fertleman et al, Neuron.; 52 (5): 767-74 (2006) Cox and colleagues (Nature, 444 (7121): 894-8 (2006) Goldberg et al, Clin Genet .; 71 (4): 311-9 (2007) Ahmad et al, Hum Mol Genet. 1; 16 (17): 2114-21 (2007)

  According to a first aspect of the invention, the compound of formula (I):

Or a pharmaceutically acceptable salt thereof, wherein:
X is O, S, NH or CH ₂ ;
Het ¹ is (i) 9-membered or 10-membered heteroaryl containing 1 to 3 nitrogen atoms, or (ii) ¹ to 3 heteroaryls independently selected from Y ¹ and Y ² A 6-membered, 9-membered or 10-membered heteroaryl containing 1 to 3 nitrogen atoms, substituted with a substituent,
Y ¹ and Y ² are independently optionally substituted with F, Cl, CN, NO ₂ , (C ₃ -C ₈ ) cycloalkyl and / or 1 to 8 Fs in the range allowed by the valence (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl optionally substituted with 1 to 8 Fs in the range allowed by valence, NR ⁷ R ⁸ , optionally independently 1 to 3 R ⁹ or (C ₁ -C ₈ ) alkyloxy, (C ₃ -C ₈ ) cycloalkyloxy, optionally independently 1 to 3 R ¹⁰ substituted with ₁ to ₈ F in the range allowed by the valence. Selected from phenoxy, Het ² , Het ² -oxy, and Het ³ optionally substituted with 1 to 3 R ¹⁰ , wherein (C ₃ -C ₈ ) cycloalkyl Oxy may optionally be fused to a phenyl ring, and May independently be substituted with 1 to 8 F and / or 1 to 3 R ¹⁰ in the range allowed by the valence;
R ¹ is (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, each of which is optionally substituted with 1 to 8 Fs in the range allowed by the valence;
R ² , R ³ , R ⁴ are independently H, F, Cl or —OCH ₃ ;
R ⁵ is H, CN, F, Cl or R ⁶
R ⁶ is a group selected from (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkyloxy, wherein each group is 1-8 Fs in the range allowed by the valence Is optionally substituted,
R ⁷ and R ⁸ are independently H, optionally independently (C ₁ -C ₈ ) alkyl optionally substituted with 1 to 3 R ¹¹ , optionally with ₁ to ₈ Fs in the range allowed by the valence. Substituted (C ₃ -C ₈ ) cycloalkyl, “C-linked” Het ² or “C-linked” Het ³ , wherein (C ₃ -C ₈ ) cycloalkyl is optionally fused to a phenyl ring. Or independently substituted with 1 to 3 R ¹⁰ , or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, is a saturated bridged 7 A 9-membered ring is formed,
R ⁹ is (C ₁ -C ₆ ) alkyloxy, (C ₃ -C ₈ ) cycloalkyl, Het ² , or optionally substituted with _{1 to} 3 F or (C ₁ -C ₆ ) alkyl. Independently phenyl substituted with 1 to 3 R ⁶ ,
R ¹⁰ is Cl, CN or R ⁶
R ¹¹ is F, (C ₁ -C ₆ ) alkyloxy, (C ₃ -C ₈ ) cycloalkyl optionally substituted with 1 to 3 F, “C-linked” Het ² , or optionally independently 1 to 3 phenyl substituted with R ⁶ ;
Het ² is a 3-8 membered saturated monoheterocycloalkyl containing 1 or 2 ring members selected from —NR ¹² — and —O—, wherein the monoheterocycloalkyl is a ring carbon atom _{1 to 1} independently selected from F, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkyloxy, (C ₀ -C ₄ ) alkylene and (C ₃ -C ₈ ) cycloalkyl Optionally substituted with 3 substituents,
Het ³ is a 5- or 6-membered heteroaryl containing 1 to 3 nitrogen atoms, the heteroaryl being 1 to 3 substituents selected from F, Cl, CN and R ⁶ And R ¹² is H, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, wherein (C ₁ -C ₆ ) alkyl and (C ₃ -C ₈ ) cycloalkyl is optionally substituted with 1 to 3 Fs or absent when Het ² is “N-linked”.

A plurality of embodiments (E) of the first aspect of the present invention will be described below. Here, for convenience, E1 is the same as the first aspect.
E1: A compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

E2: Het ¹ is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, and the heteroaryl is independently substituted with 1 to 3 substituents selected from Y ¹ and Y ² A compound according to E1.

E3: Het ¹ is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, and the heteroaryl is independently substituted with 1 or 2 substituents selected from Y ¹ and Y ² A compound according to any one of E1 and E2.

E4: The compound according to any one of E1-E3, wherein Het ¹ is pyridyl or pyrimidinyl, each independently substituted with one or two substituents selected from Y ¹ and Y ² .

E5: The compound according to any one of E1 to E4, wherein Het ¹ is pyridyl substituted with one or two substituents independently selected from Y ¹ and Y ² .
E6: Any of E1 to E5, wherein Het ¹ is pyridyl substituted with one or two substituents independently selected from Y ¹ and Y ² and the pyridyl is oriented as follows: Compounds related to:

E7: When the pyridyl is 2-substituted with Y ¹ or 3-substituted with Y ² and is 2-substituted, 2-substituted with Y ¹ and 3-substituted with Y ² Or a compound according to E6.

E8: Y ¹ is (C ₃ -C ₈ ) cycloalkyl and / or (C ₁ -C ₈ ) alkyl optionally substituted with ₁ to ₈ F in the range allowed by the valence, range allowed by the valence (C ₃ -C ₈ ) cycloalkyl optionally substituted with 1 to 8 F of the above, (C ₁ -C ₆ ) alkyloxy optionally substituted with 1 to 8 F in the range allowed by the valence , (C ₃ -C ₈ ) cycloalkyloxy, or Het ² according to any of E1 to E7.

E9: Y ¹ is (C ₃ -C ₆ ) cycloalkyl and / or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 8 F in the range allowed by the valence, range allowed by the valence (C ₃ -C ₆ ) cycloalkyl optionally substituted with 1 to 8 F of the above, (C ₁ -C ₆ ) alkyloxy optionally substituted with 1 to 8 F in the range allowed by the valence , (C ₃ -C ₈ ) cycloalkyloxy, or a 4- to 6-membered Het ² compound according to any one of E1-E8.

E10: Y ² is (C ₁ -C ₈ ) alkyl optionally substituted with F, Cl, CN, (C ₃ -C ₈ ) cycloalkyl and / or 1 to 8 F in the range allowed by the valence (C ₃ -C ₈ ) cycloalkyl optionally substituted with 1-8 F in the range allowed by the valence, optionally substituted with 1-8 F in the range allowed by the valence (C ₁ -C _{6) alkyloxy, (C} 3 ~C ₈₎ cycloalkyloxy, or Het ^2, compounds according to any one of E1 to E9.

E11: Y ² is (C ₁ -C ₄ ) alkyl optionally substituted with F, Cl, CN, (C ₃ -C ₆ ) cycloalkyl and / or 1 to 8 Fs in the range allowed by the valence (C ₃ -C ₆ ) cycloalkyl optionally substituted with 1-8 F in the range allowed by the valence, optionally substituted with 1-8 F in the range allowed by the valence (C ₁ -C _{6) alkyloxy, (C} 3 ~C ₆₎ is Het ² cycloalkyloxy or 4-6 membered ring, a compound according to any one of E1 to E10.

E12: (C ₁ -C ₄ ) alkyl optionally substituted with Y ² by F, Cl, CN, (C ₃ -C ₆ ) cycloalkyl and / or 1 to 6 Fs in the range allowed by the valence (C ₃ -C ₆ ) cycloalkyl optionally substituted with 1 to 6 Fs in the range allowed by the valence, optionally substituted with 1 to 6 Fs in the range allowed by the valence (C ₁ -C _{6) alkyloxy, (C} 3 ~C ₆₎ is Het ² cycloalkyloxy or 4-6 membered ring, a compound according to any one of E1 to E11.

E13: The compound according to any one of E1 to E12, wherein R ¹ is (C ₁ -C ₄ ) alkyl or (C ₃ -C ₆ ) cycloalkyl.
E14: The compound according to any one of E1 to E13, wherein R ¹ is (C ₁ -C ₃ ) alkyl or (C ₃ -C ₄ ) cycloalkyl.

E15: The compound according to any one of E1-E14, wherein R ¹ is methyl or cyclopropyl.
E16: The compound according to any one of E1-E15, wherein R ² , R ³ and R ⁴ are independently H, F or Cl.

E17: The compound according to any one of E1-E16, wherein R ² , R ³ and R ⁴ are independently H or F.
E18: The compound according to any one of E1-E17, wherein R ² is F and R ³ and R ⁴ are independently H or F.

E19: R ⁵ is H, CN, F, Cl, (C ₁ -C ₄ ) alkyl optionally substituted with 1 to 8 F in the range allowed by the valence, or 1 in the range allowed by the valence optionally substituted with eight F is _(C 1 _{~C 4)} alkyloxy, compounds according to any one of E1～E18.

E20: The compound according to any one of E1 to E19, wherein R ⁵ is H, CN, F, Cl, CH ₃ , C ₂ H ₅ , CF ₃ , —OCH ₃ , —OC ₂ H ₅ or —OCF ₃ . .
E21: The compound according to any one of E1 to E20, wherein R ⁵ is F or Cl.

E22: The compound according to any one of E1 to E21, wherein X is O.
E23: Examples 1-14, 4- (5-chloro-6-methoxypyridin-3-yloxy) -N- (cyclopropylsulfonyl) -2,5-difluorobenzamide, Examples 16-103, 5-chloro- 4- (6-Cyclopropyl-5- (1,1-difluoroethoxy) pyridin-3-yloxy) -2-fluoro-N- (methylsulfonyl) benzamide, any of Examples 105-201 or Examples L1-L70 Or a pharmaceutically acceptable salt thereof.

Hereinafter, a plurality of other embodiments (EM) of the first aspect of the present invention will be described.
EM1: Compound of formula (I)

Or a pharmaceutically acceptable salt thereof, wherein
X is O,
Het ¹ is (i) 9-membered or 10-membered heteroaryl containing 1 to 3 nitrogen atoms, or (ii) ¹ to 3 heteroaryls independently selected from Y ¹ and Y ² A 6-membered, 9-membered or 10-membered heteroaryl containing 1 to 3 nitrogen atoms, substituted with a substituent,
Y ¹ and Y ² are independently F, Cl, CN, (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₈ ) alkyl optionally substituted with 1 to 3 F, 1 to 3 (C ₃ -C ₈ ) cycloalkyl optionally substituted with F, NR ⁷ R ⁸ , (C ₁ -C ₈ ) alkyloxy optionally substituted with 1 to 3 R ⁹ , (C ₃ -C ₈ ) cycloalkyloxy, optionally independently selected from 1 to 3 R ¹⁰ -substituted phenyl, Het ² and Het ³ , wherein (C ₃ -C ₈ ) cycloalkyloxy is Optionally fused to a phenyl ring, or independently substituted with 1 to 3 R ¹⁰ ,
R ¹ is (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, each of which is optionally substituted with 1 to 3 F;
R ² , R ³ , R ⁴ are independently H, F, Cl or —OCH ₃ ;
R ⁵ is H, CN, F, Cl or R ⁶
R ⁶ is a group selected from (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkyloxy, wherein each group is 1-5 F in the range allowed by the valence Is optionally substituted,
R ⁷ and R ⁸ are independently H, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, optionally substituted with 1 to 3 R ¹¹ , or “C-linked” Het ² where (C ₃ -C ₈ ) cycloalkyl is optionally fused to a phenyl ring, or independently substituted with 1 to 3 R ¹⁰ , or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a saturated bridged 7-9 membered ring;
R ⁹ is F, (C ₁ -C ₆ ) alkyloxy, (C ₃ -C ₈ ) cycloalkyl optionally substituted with 1 to 3 F, Het ² , or optionally independently 1 to 3 R ⁶ substituted with R ⁶ of
R ¹⁰ is F, Cl or R ⁶ ;
R ¹¹ is F, (C ₁ -C ₆ ) alkyloxy, (C ₃ -C ₈ ) cycloalkyl optionally substituted with 1 to 3 F, “C-linked” Het ² , or optionally independently 1 to 3 phenyl substituted with R ⁶ ;
Het ² is a 3-8 membered saturated monoheterocycloalkyl containing 1 or 2 ring members selected from —NR ¹² — and —O—, wherein the monoheterocycloalkyl is a ring carbon atom _{1 to 1} independently selected from F, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkyloxy, (C ₀ -C ₄ ) alkylene and (C ₃ -C ₈ ) cycloalkyl Optionally substituted with 3 substituents,
Het ³ is a 5- or 6-membered heteroaryl containing 1 to 3 nitrogen atoms, wherein the heteroaryl is 1 to 3 substituents selected from F, Cl, CN and R ⁶ And R ¹² is H, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, wherein (C ₁ -C ₆ ) alkyl and (C ₃ -C ₈ ) cycloalkyl is optionally substituted with 1 to 3 Fs or absent when Het ² is “N-linked”.

EM2: Het ¹ is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, and the heteroaryl is independently substituted with 1 to 3 substituents selected from Y ¹ and Y ² A compound according to EM1.

EM3: Het ¹ is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, and the heteroaryl is independently substituted with 1 or 2 substituents selected from Y ¹ and Y ² A compound according to either EM1 or EM2.

EM4: A compound according to any one of EM1-EM3, wherein Het ¹ is pyridyl or pyrimidinyl, each independently substituted with one or two substituents selected from Y ¹ and Y ² .

EM5: The compound according to any one of EM1 to EM4, wherein Het ¹ is pyridyl substituted with one or two substituents independently selected from Y ¹ and Y ² .
EM6: Any of EM1 to EM5, wherein Het ¹ is pyridyl substituted with one or two substituents independently selected from Y ¹ and Y ² and the pyridyl is oriented as follows: Compounds related to:

EM7: When the pyridyl is 2-substituted with Y ¹ or 3-substituted with Y ² and is 2-substituted, 2-substituted with Y ¹ and 3-substituted with Y ² A compound according to EM6.

EM8: Y ¹ is optionally substituted with (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₈ ) alkyl optionally substituted with 1 to 3 F, 1 to 3 F ( C ₃ -C ₈₎ cycloalkyl, optionally substituted with 1-3 F _(C 1 ~C _{6) alkyloxy, (C} 3 ~C ₈₎ cycloalkyloxy, or Het ^2, EM1~ A compound according to any of EM7.

EM9: Y ¹ is optionally substituted with (C ₃ -C ₆ ) cycloalkyl or (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 3 F, 1 to 3 F ( C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkyloxy optionally substituted with 1 to 3 F, (C ₃ -C ₈ ) cycloalkyloxy, or 4-6 membered Het ² , the compound according to any one of EM1 to EM8.

^EMlO: Y 2 _{is, F, Cl, CN, (} C 3 ~C 8) optionally substituted cycloalkyl, or 1-3 F _(C 1 ~C ₈₎ alkyl, with 1-3 F Optionally substituted (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₆ ) alkyloxy optionally substituted with 1 to 3 F, (C ₃ -C ₈ ) cycloalkyloxy, or Het ² , the compound according to any one of EM1 to EM9.

EM11: Y ² is F, Cl, CN, (C ₃ -C ₆ ) cycloalkyl or (C ₁ -C ₄ ) alkyl optionally substituted with _{1 to} 3 F, 1 to 3 F Optionally substituted (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkyloxy optionally substituted with 1 to 3 F, (C ₃ -C ₆ ) cycloalkyloxy, or 4 A compound according to any one of EM1 to EM10, which is Het ² of a 6-membered ring.

EM12: The compound according to any one of EM1 to EM11, wherein R ¹ is (C ₁ -C ₄ ) alkyl or (C ₃ -C ₆ ) cycloalkyl.
EM13: The compound according to any one of EM1 to EM12, wherein R ¹ is (C ₁ -C ₃ ) alkyl or (C ₃ -C ₄ ) cycloalkyl.

EM14: The compound according to any one of EM1 to EM13, wherein R ¹ is methyl or cyclopropyl.
EM15: The compound according to any one of EM1 to EM14, wherein R ² , R ³ and R ⁴ are independently H, F or Cl.

EM16: The compound according to any one of EM1 to EM15, wherein R ² , R ³ and R ⁴ are independently H or F.
EM17: The compound according to any one of EM1 to EM16, wherein R ² is F, and R ³ and R ⁴ are independently H or F.

EM18: R ⁵ is H, CN, F, Cl, (C ₁ -C ₄ ) alkyl optionally substituted with 1-3 F, or optionally substituted with 1-3 F (C _{1 to} C ₄ ) A compound according to any one of EM1 to EM17, which is alkyloxy.

EM19: The compound according to any one of EM1 to EM18, wherein R ⁵ is H, CN, F, Cl, CH ₃ , C ₂ H ₅ , CF ₃ , —OCH ₃ , —OC ₂ H ₅ or —OCF ₃ . .
EM20: The compound according to any one of EM1 to EM19, wherein R ⁵ is F or Cl.

  Alkyl, alkylene and alkoxy groups containing the requisite number of carbon atoms may be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene and 2,2-propylene.

Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Halo means fluoro, chloro, bromo or iodo.

  The term “C-linked” as used in the definition of formula (I) means that the group is linked by a ring carbon. The term “N-linked” as used in the definition of formula (I) means that the group is linked by a ring nitrogen.

  Specific examples of 5- or 6-membered heteroaryl used in the definition of formula (I) include pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. Except where expressly expressed as described above, when such heteroaryl is substituted, the substituent may be a ring carbon (in all cases) or a ring nitrogen with the appropriate valence (substituted) (When the group is linked by a carbon atom).

  Specific examples of the 9-membered or 10-membered heteroaryl used in the definition of the formula (I) include indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo [2,3-b] pyridyl, pyrrolo [2,3-c] pyridyl, pyrrolo [3,2-c] pyridyl, pyrrolo [3,2-b] pyridyl, imidazo [4,5-b] pyridyl, imidazo [4,5-c] pyridyl, pyrazolo [4,3-d] pyridyl, pyrazolo [4,3-c] pyridyl, pyrazolo [3,4-c] pyridyl, pyrazolo [3,4-b] pyridyl, isoindolyl, indazolyl, purinyl, indolizinyl, imidazo [1 , 2-a] pyridyl, imidazo [1,5-a] pyridyl, pyrazolo [1,5-a] pyridyl, pyrrolo [1,2-b] pyridazinyl, imidazo [1,2 c] pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7- Naphthyridinyl, pyrido [3,2-d] pyrimidinyl, pyrido [4,3-d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrido [2,3-d] pyrimidinyl, pyrido [2,3-d] And pyrazinyl and pyrido [3,4-b] pyrazinyl. Except where expressly expressed as described above, when such a heteroaryl is substituted, the substituent may be a ring carbon (in all cases) or a ring nitrogen having the appropriate valence ( (When the substituent is linked by a carbon atom).

Specific examples of Het ² include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, oxepanyl, oxazepanyl and diazepinyl.

  Hereinafter, all references to compounds of the present invention include compounds of formula (I) or pharmaceutically acceptable salts, solvates or multicomponent complexes thereof, or of formula (I) as described in more detail below. It includes pharmaceutically acceptable solvates or multicomponent complexes of pharmaceutically acceptable salts of the compounds.

A preferred compound of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Suitable acid addition salts are formed from acids that form non-toxic salts. For example, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansylate, citrate, cyclamate , Edicylate, esylate, formate, fumarate, gluconate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / Bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthylate, nicotinic acid Salt, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, sugar salt, stearate, succinate, tannin Acid salt, tartrate salt, Le salts include trifluoroacetate and Kishinoho salts.

  Suitable basic salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Moreover, the acid and base half salt may be formed, for example, from a hemisulfate and a half calcium salt.
For those skilled in the art, the salt may have a counterion that is optically active (eg, d-lactate or l-lysine) or also contains a racemate (eg, dl-tartrate or dl-arginine). I know.

  For an overview on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). I want.

Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of the following three methods:
(I) reacting a compound of formula (I) with the desired acid or base;
(Ii) removing the acid or base labile protecting group from a suitable precursor of the compound of formula (I) using the desired acid or base, or (iii) reacting with a suitable acid or base or preferred One ion exchange column is used to convert one salt of the compound of formula (I) to another salt.

  Usually all three reactions are carried out in solution. The resulting salt may be deposited and recovered by filtration, or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt may vary from fully ionized to almost non-ionized.

The compound of formula (I) or a pharmaceutically acceptable salt thereof may exist in both unsolvated and solvated forms. The term “solvate” refers to a molecular complex comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules (eg, ethanol). As used herein. The term “hydrate” is used when the solvent is water. Pharmaceutically acceptable solvates in accordance with the present invention, the solvent of crystallization may be isotopically substituted, _e.g., D 2 _O, d 6 _- and acetone, and d _6-DMSO.

  The currently recognized classification system for organic hydrates is to define isolated sites, channels or metal ion coordination hydrates, and “Polymorphism in Pharmaceutical Solids” By KR Morris (Ed. HG Brittain, Marcel Dekker, 1995), the contents of which are incorporated herein by reference. Isolated site hydrates are those in which water molecules are isolated from direct contact with each other through the intervention of organic molecules. In channel hydrates, water molecules are in lattice channels, in which the water molecules are adjacent to each other. In metal ion coordination hydrate, water molecules are bound to metal ions.

  If the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. However, if the solvent or water is weakly bound, as with channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry is the standard.

  The compounds of the present invention may exist in a series of solid states from a completely amorphous state to a completely crystalline state. The term “amorphous” refers to a state in which a material lacks long-range order at the molecular level and can exhibit solid or liquid properties depending on temperature. Typically, such materials do not give a characteristic X-ray diffraction pattern and are more formally represented as a liquid while exhibiting solid properties. Upon heating, a change from solid to liquid properties occurs, which is characterized by a change in state, typically a second order phase transition (“glass transition”). The term “crystalline” refers to a solid phase that gives a characteristic X-ray diffraction pattern in which the material has a regular internal structure at the molecular level and has distinct peaks. Such materials also exhibit liquid properties when fully heated, but the change from solid to liquid is characterized by a phase change, typically a first order phase transition ("melting point").

  Multi-component complexes (salts and solvates) of a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts Other than the above is also included in the scope of the present invention. Examples of this type of complex include an inclusion body (an inclusion complex between a drug and a host) and a co-crystal. The latter is typically defined as a crystalline complex of neutral molecular components joined together by non-covalent interactions, but may be a complex of neutral molecule and salt. Co-crystals may be prepared by melt crystallization, recrystallization from solvents, or by physically grinding the ingredients together, Chem Commun, 17, 1889-1896, by O. Almarsson and MJ Zaworotko (2004 ), The contents of which are incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975), the contents of which are hereby incorporated by reference.

The compounds of the present invention may also exist in a mesomorphic state (mesophase or liquid crystal) when exposed to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Liquid crystallinity caused by temperature changes is referred to as “thermotropic”, and liquid crystallinity caused by the addition of a second component such as water or another solvent is termed “lyotropic”. Compounds that can form lyotropic mesophases are termed “amphiphilic” and are ionic (such as —COO ⁻ Na ⁺ , —COO ⁻ K ⁺ or —SO ₃ ⁻ Na ⁺ ) or nonionic (− N ^— N ⁺ (CH ₃ ) ₃ etc.) composed of molecules having polar head groups. Additional information, reference is made to the detailed Crystals and the Polarizing Microscope (crystal and polarizing microscope) by NH Hartshorne and A. Stuart, 4 th Edition (Edward Arnold, 1970), the contents of which are incorporated herein by reference.

  The compounds of the present invention may be administered as prodrugs. Thus, certain derivatives of a compound of formula (I), which themselves may have little or no pharmacological activity, are administered to the desired activity, for example by hydrolysis, when administered in or on the body. Can be converted to compounds of formula (I) having: Such derivatives are referred to as “prodrugs”. For more information on the use of prodrugs, see “Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and“ Bioreversible Carriers in Drug Design ( Bioreversible carriers in drug design) ", Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association).

  For example, as described in “Design of Prodrugs” by H Bundgaard (Elsevier, 1985), suitable functional groups present in compounds of formula (I) can be represented by “pro moieties”, for example. Prodrugs can be made by substituting with specific moieties known to those skilled in the art, such as

  Examples of prodrugs include phosphate prodrugs such as dihydrogen phosphate or dialkyl phosphate (eg, di-tert-butyl) prodrugs. Further examples of substituents according to the above examples and other prodrug type examples are described in the above references.

  Also included within the scope of the invention are metabolites of the compound of formula (I), ie, compounds formed in vivo upon administration of the drug. Some examples of metabolites according to the present invention include phenol derivatives (-Ph> -PhOH) when the compound of formula (I) contains a phenyl (Ph) moiety.

  Compounds of the present invention that contain one or more asymmetric carbon atoms can exist as two or more stereoisomers. All stereoisomers of the compounds of the present invention and mixtures of one or more thereof are included within the scope of the present invention.

  Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or racemates (or salts using, for example, chiral high performance liquid chromatography (HPLC)). Or a racemic derivative of the derivative).

  Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound (eg, alcohol) or, if the compound of formula (I) contains an acidic or basic moiety, 1-phenylethylamine Or you may make it react with bases or acids, such as tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers may be separated by a means well known to those skilled in the art by the corresponding pure one or more The enantiomers of

  The chiral compound of the present invention (and its chiral precursor) is mixed with 0-50% by volume, typically 2% -20% by volume 2-propanol, and 0-5% by volume alkylamine, typically Using a mobile phase consisting of a hydrocarbon containing 0.1% by volume diethylamine, typically heptane or hexane, and enantiomerically using chromatography packed typically with an asymmetric resin, typically HPLC. It may be obtained in a concentrated form. Depending on the concentration of the eluent, a concentrated mixture is obtained.

  Stereoisomeric mixtures may be separated by conventional techniques known to those skilled in the art, for example, “Stereochemistry of Organic Compounds” by EL Eliel and SH Wilen (Wiley, New York, 1994).

  The scope of the present invention includes all crystal forms of the compounds of the present invention, such as racemates and racemic mixtures (aggregates) thereof. Alternatively, stereoisomeric aggregates may be separated by the prior art described in this specification.

  The scope of the present invention is isotopically labeled in which one or more atoms are replaced with atoms having the same atomic number but having an atomic mass or mass number different from the naturally occurring atomic mass or mass number. All pharmaceutically acceptable compounds of the present invention.

Suitable isotopes for inclusion in the compounds of the present invention include, for example, hydrogen such as ² H and ³ H, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ Cl, fluorine such as ¹⁸ F , Iodine such as ¹²³ I and ¹²⁵ I, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus such as ³² P and sulfur isotopes such as ³⁵ S.

In one aspect, the isotopically labeled compound of formula (I) contains one or more deuterium atoms. In another embodiment, Y ¹ and / or Y ² are independently (C ₁ -C ₈ ) alkyl or (C ₁ -C ₈ ) alkyloxy, wherein one or more hydrogen atoms are replaced with deuterium atoms Yes.

Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes are incorporated, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (ie ³ H) and carbon 14 (ie ¹⁴ C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes, such as deuterium (ie ² H), certain therapeutic benefits derived from greater metabolic stability, such as increased in vivo half-life or reduced dose required And thus may be preferred in some situations. Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy.

  Isotopically-labelled compounds of formula (I) are generally attached to the prior art using known isotope-labeled reagents instead of conventional techniques known to those skilled in the art or previously used unlabeled reagents. It can be prepared in a manner analogous to that described in the Examples and Preparation Examples.

  The intermediate compounds defined below, all salts, solvates and complexes thereof, as well as all solvates and complexes of salts thereof defined below for compounds of formula (I) Is within the range. The present invention includes all polymorphs of the above chemical species and crystal habits thereof.

  When preparing the compounds of formula (I) according to the invention, the person skilled in the art may routinely select an intermediate form that provides the best combination of features for this purpose. Such features include melting point, solubility, manufacturability and yield of intermediate forms and consequently the product can be easily purified by isolation.

  The compounds of the present invention may be prepared by any method known in the art for the preparation of compounds of similar structure. In particular, the compounds of the present invention can be prepared by procedures described with reference to the following schemes, specific methods described in the Examples, or methods similar to either one of them.

  Those skilled in the art will appreciate that the experimental conditions described in the following schemes are examples of conditions suitable for carrying out the illustrated transformation, and detailed conditions used for the preparation of compounds of formula (I). It will be appreciated that changes may be necessary or desirable. It may be necessary or desirable to perform the transformations in a different order than described in the scheme or to modify one or more of the transformations to obtain the desired compounds of the invention. You will understand further.

  Furthermore, those skilled in the art will recognize that it may be necessary or desirable to protect one or more sensitive groups at any stage in the synthesis of the compounds of the invention to prevent undesirable side reactions. Will. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the present invention may be used in a conventional manner. For example, “Greene's Protective Groups in Organic Synthesis” by Theodora W Greene and Peter GM Wuts, third edition, (John Wiley and Sons, 1999), especially Chapter 7 ( See “Protection for the Amino Group”) and Chapter 5 (“Protection for the Carboxyl Group”), the contents of which are incorporated herein by reference and there Describes a method for removing such groups.

In the following general methods, unless otherwise indicated, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Het ¹ are as defined above for compounds of formula (I). . Pg is a suitable carboxylic acid protecting group such as tert-butyl, methyl, ethyl or tolyl. Lg is a suitable leaving group such as halo (eg Br) or sulfonate (eg mesylate, triflate or tosylate). E is aldehyde or nitrile or Lg.

Where solvent ratios are given, those ratios are based on volume.
One skilled in the art may perform the synthetic steps described below in any suitable order to arrive at the compound of formula (I).

  According to the first method, compounds of formula (I) wherein X is O, NH or S may be prepared by the method illustrated in Scheme 1.

  The compound of formula (I) can be prepared from the compound of formula (III) by replacing the ester with the compound of formula (VI) and a suitable base according to preparation step (v). Suitable conditions include 60 ° C. potassium tert-butoxide in THF, 65 ° C. NaH in THF, and 50 ° C. potassium carbonate and DBU in DMSO. A more preferable condition is an acetonitrile solution of DBU at 50 ° C.

  Alternatively, according to the reaction step (vi), the acidic group is activated with a reagent such as oxalyl chloride, carbonyldiimidazole (CDI), a uronium-based peptide coupling agent or a carbodiimide reagent, and then a 4-dimethylaminopyridine or the like is obtained. A compound of formula (I) can be prepared from a compound of formula (II) by displacement with a sulfonamide of formula (VI) in the presence of a nucleobase. Preferred conditions include N, N-dimethylaminopropyl-N′-ethylcarbodiimide and 4-dimethylaminopyridine in DCM at 65 ° C., hexafluorophosphoric acid N-[(dimethylamino) (3H- [1,2 , 3] triazolo [4,5-b] pyridin-3-yloxy) methylene] -N-methylmethanaminium and N-ethyl-N-isopropylpropan-2-amine in DCM or 2,4,6-tri A THF solution of propyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide and N-ethyl-N-isopropylpropan-2-amine is included.

  Compounds of formula (I) can also be prepared from compounds of formula (V) by reversing production steps (iii) and (vi). Preferred conditions for the production step (iii) are as described for the following production step (ii), and preferred conditions for the production step (vi) include a 90 ° C. DMSO solution of potassium carbonate or 60 ° C. of NaH. In THF.

  The compound of formula (III) can be prepared from the compound of formula (IV) by aromatic nucleophilic substitution reaction (SNAr) using the compound of formula (VII) and a base according to production step (ii). Suitable conditions include potassium carbonate in DMF or DMSO at 120 ° C., sodium hydride in NMP or DMF, and sodium hydroxide or potassium hydroxide in 1,4-dioxane and water or DMSO, or potassium tert -A solution of butoxide in THF or a pyridine solution of cesium carbonate and copper powder. Preferred conditions include 2 equivalents of potassium carbonate in DMSO at room temperature.

  According to manufacturing step (i), the compound of formula (IV) can be prepared from the compound of formula (V) using the protecting group method in “Greene's Protective Groups in Organic Synthesis” as referenced above. . When Pg is tolyl, preferred conditions include 50 ° C. thionyl chloride using para-cresol. When Pg is tert-butyl, preferred conditions include di-tert-butyl dicarbonate and tert-butanol solution of 4-dimethylaminopyridine.

  The compound of formula (II) can be prepared from the compound of formula (III) by hydrolysis of the ester under basic or acidic conditions according to production step (iv). Preferred conditions are sodium hydroxide in MeOH and THF or lithium hydroxide in THF and water, or room temperature TFA in DCM.

  Alternatively, according to the production step (iii), the compound of formula (II) is converted to the formula (II) by the aromatic nucleophilic substitution reaction (SNAr) using the compound of formula (VII) and the base described for the high temperature production step (ii). V) can be prepared from compounds. Preferred conditions include a 90 ° C. DMSO solution of potassium carbonate.

  According to the second method, compounds of formula (I) wherein X is O, NH or S may be prepared by the method illustrated in Scheme 2.

  When E is a nitrile, according to reaction step (viii), the nitrile is hydrolyzed to the primary carboxamide by either acid or base method and then reacted with the appropriate sulfonyl chloride of formula (XI), Compounds of formula (I) can be prepared from compounds of formula (XII). Preferred conditions include a solution of hydrogen peroxide and potassium carbonate in DMSO, followed by a solution of lithium hexamethyldisilazide in THF, at a temperature from room temperature to 60 ° C.

  Alternatively, when E is a nitrile, according to reaction step (iv), the nitrile is hydrolyzed to a carboxylic acid by either acid or base method and then according to the production step (vi), with a sulfonamide of formula (VI) By substitution, compounds of formula (I) can be prepared from compounds of formula (XII). Preferred conditions for both steps are described in corresponding steps (iv) and (vi) of Scheme 1.

  When E is an aldehyde, a compound of formula (I) can be prepared from a compound of formula (XII) according to manufacturing step (ix), ie (oxidative rhodium insertion reaction using a compound of formula (VI) Preferred conditions include 55 of methanesulfonamide, bis (tert-butylcarbonyloxy) iodobenzene and bis [rhodium (α, α, α ′, α′-tetramethyl-1,3-benzenedipropionic acid)]. Contains isopropyl acetate solution at 0 ° C.

  When E is Lg such as Br, I or triflate, the compound of formula (I) is converted from the compounds of formula (XII) and (VI) by carboamidation after the carbonylation reaction according to production step (x). Can be prepared. In a solvent such as THF, NMP or 1,4-dioxane, under pressure or microwave irradiation at 50 to 150 ° C. for 10 minutes to 24 hours, a carbonyl source such as molybdenum hexacarbonyl or carbon monoxide, trans-bis acetate ( Acetate) bis [o- (di-o-tolylphosphino) benzyl] dipalladium (II) and the like, a phosphine ligand such as tri-tert-butylphosphonium tetrafluoroborate, and a base such as triethylamine It is convenient to carry out the reaction. Preferred conditions include molybdenum hexacarbonyl, trans-bis (acetato) bis [o- (di-o-tolylphosphino) benzyl] dipalladium (II) acetate, tri-tert-butylphosphonium tetrafluoroborate and 1,8- It includes microwave irradiation for 15 minutes at 140 ° C. using a 1,4-dioxane solution of diazabicyclo [5.4.0] undec-7-ene.

  According to the production step (ii) or (iii), the corresponding production step is carried out by the aromatic nucleophilic substitution reaction (SNAr) with the compound of formula (VII) and the base using the conditions described in Scheme 1. A compound of (XII) can be prepared from a compound of formula (XIII).

According to the third method, compounds of formula (I) in which X is CH ₂ may be prepared by the method illustrated in Scheme 3.

  According to production step (xi), a compound of formula (I) can be prepared from a compound of formula (XIV) under a Suzuki cross-coupling reaction using a compound of formula (XV) and a suitable catalyst. Typical conditions include 65 ° C. palladium tetrakistriphenylphosphine and potassium carbonate dissolved in water and THF.

According to a fourth method, X is O, NH or S by the interconversion from the corresponding compound of formula (I) wherein Y ¹ is F by the method illustrated in Scheme 4 and Y ¹ Is selected from R ⁷ R ⁸ N, (C ₁ -C ₈ ) alkyloxy, and (C ₃ -C ₈ ) cycloalkyloxy, optionally independently substituted with 1 to 3 R ⁹ , and R ⁷ Compounds of formula (I) may be prepared where R ⁸ and R ⁹ are as defined above.

In accordance with production step (xii), fluorine is replaced with a compound of formula (XVI) and a base, and a compound of formula (I) wherein Y ¹ is other than F is converted to a corresponding compound of formula (I) wherein Y ¹ is F. It may be prepared from a compound. Suitable conditions for such interconversion of compounds of formula (I) include room temperature to hot THF solution of sodium hydride, hot DMSO solution of triethylamine or 100 ° C. DMSO solution of cesium carbonate.

Those skilled in the art, in order to obtain a compound of the formula Y ¹ is other than F (I), a precursor of the fluorinated pyridyl be mono- or di-substituted with Y ¹ other than F Formula (I) It will be appreciated that the same interconversion method can be performed on body compounds.

Similarly, those skilled in the art will appreciate that the above interconversion is equally applicable to the introduction of Y ² other than F.
According to a fifth method, a compound of formula (III) wherein X is S may be prepared by the method illustrated in Scheme 5.

  A compound of formula (III) can also be prepared from a compound of formula (IV) by an aromatic nucleophilic substitution reaction with a compound of formula (XVII) and a base according to production step (xiii). Suitable conditions include room temperature potassium carbonate in DMSO.

  According to a sixth method, a compound of formula (III) in which X is O, NH or S may be prepared by the method illustrated in Scheme 6.

  Prepare a compound of formula (III) from a compound of formula (XVIII) by substituting a suitable leaving group with a compound of formula (VII) under the Buchwald-Hartwig cross coupling conditions according to the production step (xiv) You can also. Typical conditions include 110 ° C palladium acetate, BrettPhos and potassium carbonate dissolved in tert-butanol and water.

  According to a seventh method, a compound of formula (III) in which X is O, NH or S may be prepared by the method illustrated in Scheme 7.

  According to the manufacturing step (xv), a suitable leaving group is substituted with a compound of formula (XX) under Buchwald-Hartwig cross-coupling conditions (eg as described above with respect to Scheme 6) or aromatic nucleophilic substitution The compound of formula (III) can also be prepared from the compound of formula (XIX) by reaction (SnAr). Typical conditions include a 60 ° C. DMSO solution of potassium carbonate.

  Compounds of formula (V) (VI), (VII), (XI), (XIII), (XIV), (XVI), (XVII), (XVIII), (XIX) and (XX) are commercially available. Can be easily prepared by methods well known to those skilled in the art, or can be prepared according to the preparative examples described herein.

All novel synthetic methods of the compounds of formula (I) and the corresponding novel intermediates used in such methods form a further aspect of the invention.
The compounds of the present invention for pharmaceutical use may be administered as crystalline or amorphous products or exist in a series of solid states from a completely amorphous state to a completely crystalline state. It may be. They may be obtained by methods such as precipitation, crystallization, lyophilization, spray drying or evaporation drying, for example as a solid mass, powder or film. Microwave or radio frequency drying may be used for this purpose.

  The compounds may be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or as any combination thereof). Generally, the compound is administered as a formulation together with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingredient other than one or more compounds of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability and the nature of the dosage form.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention together with one or more pharmaceutically acceptable excipients.
Pharmaceutical compositions suitable for delivery of the compounds of the present invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation are described, for example, in “Remington's Pharmaceutical Sciences”, 19th Edition (Mack Publishing Company, 1995).

Suitable modes of administration include oral, parenteral, topical, inhalation / intranasal, rectal / vaginal, and ocular / ear administration.
Formulations suitable for the above modes of administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

  The compounds of the present invention may be administered orally. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, and intraoral or sublingual administration where the compound enters the bloodstream directly from the mouth may be used. Formulations suitable for oral administration include tablets, microparticles, capsules containing liquids or powders, troches (including liquids), chewable tablets (chew), multiparticulates and nanoparticles, gels, solid solutions, liposomes, films, small Examples include solid formulations such as ovules, sprays, liquid formulations and oral / mucoadhesive patches.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules, typically with a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil and one or more. Emulsifiers and / or suspending agents. A liquid formulation may also be prepared, for example, by reconstituting a solid from a sachet.

  In addition, the compounds of the present invention can be rapidly dissolved as described in “Expert Opinion in Therapeutic Patents”, 11 (6), 981-986, by Liang and Chen (2001). Or fast disintegrating dosage form.

  For tablet dosage forms, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form, depending on dose. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch And sodium alginate. Generally, the disintegrant constitutes 1% to 25%, preferably 5% to 20% by weight of the dosage form.

  Binders are generally used to provide binding properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, saccharides, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets can also be made from lactose (such as monohydrate, spray-dried monohydrate and anhydride), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. It may contain a diluent such as a product.

  Tablets may optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant may comprise 0.2% to 5% by weight of the tablet and the glidant may comprise 0.2% to 1% by weight of the tablet. Good.

  Tablets generally also contain a lubricant, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants generally constitute 0.25% to 10%, preferably 0.5% to 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and flavoring agents.

  Exemplary tablets have up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegration. And about 0.25 wt% to about 10 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Alternatively, the tablet mixture or part of the mixture may be wet, dry or melt granulated, melt set or extruded prior to tableting. The final formulation may contain one or more layers and may be coated or uncoated and further encapsulated. Tablet formulations are described in “Pharmaceutical Dosage Forms: Tablets”, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

  Suitable modified release formulations for the purposes of the present invention are described in US Pat. No. 6,106,864. For details on other suitable release technologies such as high energy dispersion and osmotic and coated particles, see “Pharmaceutical Technology On-line”, 25 (2), 1-14, by Verma et al. (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

  The compounds of the present invention may also be administered directly into the bloodstream, muscle or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Devices suitable for parenteral administration include syringes with needles (including microneedles), syringes without needles and infusion techniques.

  Parenteral preparations are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffers (preferably pH 3-9), but for some applications, as sterile non-aqueous solutions or as sterile More preferably, it is formulated as a dry form for use with a suitable medium such as pyrogen-free distilled water.

Using standard pharmaceutical techniques well known to those skilled in the art, the preparation of parenteral formulations in aseptic conditions, such as by lyophilization, may be readily accomplished.
Appropriate formulation techniques, such as incorporating solubility enhancers, may be used to increase the solubility of the compounds of formula (I) used in the preparation of parenteral solutions. Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. Accordingly, the compounds of the present invention may be formulated as a solid, semi-solid or thixotropic liquid for administration as an implantable sustained release agent that provides controlled release of the active compound. Examples of such formulations include drug-coated stents and poly (dl-lactic-coglycolic acid) (PGLA) microspheres.

  The compounds of the present invention may also be administered topically to the skin or mucosa, that is, transdermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sprays, bandages, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Is mentioned. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated, see for example J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).

  Other means of topical administration include electroporation, iontophoresis, sonophoresis, ultrasound introduction, and delivery by injection with microneedles or needles (eg Powderject ™, Bioject ™, etc.). Can be mentioned.

  The compound of the present invention is typically in the form of a dry powder from a dry powder inhaler (alone, as a mixture, eg, a dry mixture with lactose, or mixed with a phospholipid, eg, phosphatidylcholine) As particles) or using a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane or not It can also be administered intranasally or by inhalation as an aerosol spray from a pressurized container, pump, spray, nebulizer (preferably nebulizer using electrohydrodynamics that produces a fine mist) or inhaler. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, nebulizers or inhalers, for example, ethanol, aqueous ethanol, or other agents suitable for dispersing, solubilizing or sustained release of active agents and one or more jets as solvents Contains a solution or suspension of one or more compounds of the invention comprising an agent and any surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be accomplished by any suitable comminuting method, such as spiral jet mill, fluid bed jet mill, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

  Blisters and cartridges used in capsules (for example made of gelatin or hydroxypropylmethylcellulose), inhalers or insufflators, with a compound of the invention and a suitable powder base such as lactose or starch, -It may be formulated to contain a powder mixture with a performance modifier such as leucine, mannitol or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

  Suitable solution formulations used in nebulizers that use electrohydrodynamics to generate fine mists may contain from 1 μg to 20 mg of the compound of the invention per actuation, with an operating volume of 1 μl to 100 μl It may be a range. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Other solvents that can be used in place of propylene glycol include glycerin and polyethylene glycol.

  Suitable flavoring agents such as menthol and levomenthol or sweetening agents such as saccharin or saccharin sodium may be added to the formulations of the present invention for inhalation / intranasal administration.

  In the case of dry powder inhalers and aerosols, the dosage unit is measured by a valve to deliver a metered amount. Units according to the present invention are typically configured to administer a metered dose or “puff” containing 1 μg to 100 mg of a compound of formula (I). The total daily dose typically ranges from 1 μg to 200 mg, which may be administered as a single dose or, more usually, as divided doses throughout the day.

  The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, vaginal suppository, bactericidal agent, vaginal ring or enemas. Cocoa butter is a traditional suppository base, but various alternatives may be used as needed.

  The compounds of the present invention may also be administered directly to the eye or ear, typically in the form of a micronized suspension or solution drop in sterile isotonic pH-adjusted saline. Good. Other formulations suitable for ocular and otic administration include ointments, biodegradable (eg absorbable gel sponges, collagen) and non-biodegradable (eg silicone) implants, wafers, lenses and particulate systems or niosomes or Examples include vesicular systems such as liposomes. Cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymer compounds such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymer compounds such as gellan gum are benzalkonium chloride It may be incorporated with a preservative such as. Such formulations may also be delivered by iontophoresis.

  In order to improve their solubility, dissolution rate, taste-masking, bioavailability and / or stability for use in any of the above modes of administration, the compounds of the present invention are It may be combined with soluble polymer entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymer compounds.

  Drug-cyclodextrin complexes have been found to be generally useful, for example, for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. Instead of direct complexation with the drug, cyclodextrin may be used as an auxiliary additive, ie as a carrier, diluent or solubilizer. For these purposes, α-, β- and γ-cyclodextrins are most commonly used, examples of which are WO 91/11172, 94/02518 and 98/55148. In the issue.

  For administration to human patients, the total daily dose of the compounds of the invention will typically range from 1 mg to 10 g, such as from 10 mg to 1 g, such as from 25 mg to 500 mg, depending of course on the mode of administration and efficacy. is there. For example, oral administration may require a total daily dose of 50 mg to 100 mg. The total daily dose may be administered in single or divided doses and may be outside the typical ranges set forth herein at the physician's discretion. These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. A physician will readily be able to determine doses for subjects with weights outside this range, such as infants and the elderly.

  As described above, the compounds of the present invention are useful because they exhibit pharmacological activity in animals, ie, Nav1.7 channel inhibition. More particularly, the compounds of the present invention are useful in the treatment of disorders where a Nav1.7 inhibitor is required. Preferably, the animal is a mammal, more preferably a human.

In a further aspect of the invention there is provided a compound of the invention for use as a medicament.
In a further aspect of the invention, the compounds of the invention are provided for the treatment of disorders where a Nav1.7 inhibitor is required.

In a further aspect of the invention, there is provided the use of a compound of the invention for the preparation of a therapeutic for a disorder where a Nav1.7 inhibitor is required.
In a further aspect of the invention, a disorder in said animal in which a Nav1.7 inhibitor is required comprising administering to the animal (preferably a mammal, more preferably a human) a therapeutically effective amount of a compound of the invention. A method of treatment is provided.

Disorders for which a Nav1.7 inhibitor is required include pain, particularly neuropathic, nociceptive and inflammatory pain.
Physiological pain is an important defense mechanism designed to warn of danger from stimuli that can be harmful from the outside environment. The system is activated by a specific cluster of primary sensory neurons and is activated by noxious stimuli through a peripheral transduction mechanism (for review see Millan, 1999, Prog. Neurobiol., 57, 1-164) ). These sensory fibers are known as nociceptors and are characterized by small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of nociceptive stimuli by their topographically organized projections onto the spinal cord (ie, stimulation location). Nociceptors are present in nociceptive nerve fibers, which are of two major types, Aδ fibers (myelinated) and C fibers (unmyelinated). The activity generated by nociceptor input is transmitted to the cortex where, after complex processing in the dorsal horn, either directly or via the brainstem relay nucleus, the thalamic musculoskeletal (ventrobasal thalamus) is then generated. Is done.

  Pain can generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually 12 weeks or less). Acute pain is usually associated with a specific cause, such as a specific injury, and is often severe and severe. Acute pain is a type of pain that can occur after certain injuries resulting from surgery, dental treatment, contusion or sprain. Acute pain generally does not cause any sustained psychological reaction. In contrast, chronic pain is long-term pain, typically lasting more than 3 months, resulting in significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (eg painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, joint pain and chronic postoperative pain It is.

  When large damage is caused to a body tissue by disease or trauma, the properties of nociceptor activation change and sensitization occurs at the periphery, locally around the injury and at the center where the nociceptor terminates. These effects cause an increase in pain sensation. In acute pain, these mechanisms can be useful in promoting defensive behavior, which can better initiate the repair process. Usually, the sensitivity is expected to return to normal once the injury has healed. However, in many chronic pain states, hypersensitivity further prolongs the healing process, often due to nervous system damage. This damage often causes abnormalities in sensory nerve fibers with maladaptation and abnormal activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

  Clinical pain is present when discomfort and abnormal susceptibility occupy a significant position in the patient's symptoms. Patients tend to be very heterogeneous and can exhibit various pain symptoms. Such symptoms include 1) for example, dull, tingling or piercing spontaneous pain, 2) excessive pain response to noxious stimuli (hyperalgesia), and 3) pain caused by normally harmless stimuli. (Allodynia-Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the basic mechanisms are probably different and therefore may require different treatment strategies. Thus, pain can be divided into a number of different subtypes including nociceptive, inflammatory and neuropathic pain according to different pathophysiology.

  Nociceptive pain is induced by tissue damage or by strong stimuli that can cause damage. Pain afferent nerves are activated by the transmission of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at their terminal stage. The stimulus is then transmitted through the spinal tract to the brain where pain is recognized (Meyer et al., 1994, Textbook of Pain, 13-44). Activation of nociceptors activates two types of afferent nerve fibers. Myelinated Aδ fibers transmit quickly and are involved in the sensation of intense pain and piercing pain, while unmyelinated C fibers transmit at a slower rate and transmit dull or tingling pain. Moderate to severe acute nociceptive pain includes central nervous system trauma, contusion / sprain, burns, myocardial infarction and acute pancreatitis, postoperative pain (pain after any type of surgical procedure), posttraumatic pain, kidney Prominently characterized by pain due to colic, cancer pain and back pain. Cancer pain is pain associated with cancer treatment (eg, postchemotherapy syndrome, chronic pain, such as tumor-related pain (eg, bone pain, headache, facial pain or visceral pain) It may be postoperative pain syndrome or post radiation syndrome. Cancer pain may occur in response to chemotherapy, immunotherapy, hormonal therapy or radiation therapy. Back pain may be due to abnormalities in the prolapsed or ruptured disc or lumbar facet joint, sacroiliac joint, paraspinal muscle or posterior longitudinal ligament. Back pain may heal spontaneously, but in some patients, back pain can last for more than 12 weeks and become a chronic disease that can be particularly debilitating.

  Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or nervous system dysfunction. Because nerve damage can be caused by trauma and disease, the term “neuropathic pain” encompasses many disorders with a variety of causes. Such disorders include peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain As well as pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiencies. Neuropathic pain is pathological because it has no protective role. Neuropathic pain is often still present after the first cause disappears and generally persists for many years, significantly reducing the patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964 ). Symptoms of neuropathic pain are difficult to treat, even among patients suffering from the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). Neuropathic pain includes spontaneous pain that can be continuous and paroxysmal or abnormally induced pain such as hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to normally harmless stimuli) .

  The inflammatory process is a complex series of biochemical and cellular events that are activated in response to tissue damage or the presence of foreign bodies, thereby causing swelling and pain (Levine and Taiwo, 1994, Textbook of Pain , 45-56). Joint pain is the most common inflammatory pain. Rheumatoid disease is one of the most common chronic inflammatory diseases in developed countries, and rheumatoid arthritis is a common cause of disability. The exact cause of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be influential (Grennan & Jayson, 1994, Textbook of Pain, 397-407 ). It is estimated that nearly 16 million Americans suffer from symptomatic osteoarthritis (OA) or osteoarthritis, most of which are over 60 years old, and as the age of the population increases, This number is expected to increase to 40 million, a huge public health problem (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek treatment because of the associated pain. Arthritis has a major impact on psychosocial and physical functions and is known to be a major cause of disability in later years. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from an intermittent onset of back pain that occurs throughout life to a severe chronic disease that attacks the spine, peripheral joints and other human organs.

  Another type of inflammatory pain is visceral pain, including pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, including the organs of the abdominal cavity. These organs include the genitals, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly experienced gastrointestinal (GI) disorders that cause pain include functional bowel disease (FBD) and inflammatory bowel disease (IBD). These GI disorders include a wide range of conditions that are currently somewhat suppressed, such as gastroesophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS). : functional abdominal pain syndrome), and for IBD include Crohn's disease, ileitis and ulcerative colitis, all of which regularly cause visceral pain. Other types of visceral pain include dysmenorrhea, cystitis and pancreatitis and pain associated with pelvic pain.

  Some types of pain have multiple causes and can therefore be classified into more than one area, for example, back pain and cancer pain have both nociceptive and neuropathic elements It should also be noted.

Other types of pain include the following:
Pain caused by skeletal muscle disorders including myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatic) arthropathy, extra-articular rheumatism, dystrophin abnormalities, glycogenolysis, polymyositis and purulent myositis,
Cardiac and vascular pain, including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, edematous sclerosis and skeletal muscle ischemia,
Migraine (including migraines with and without aura), cluster headaches, tension-type headaches, mixed headaches, and headaches related to vascular disorders,
・ Red limb pain,
Orofacial pain including toothache, ear pain, oral burning syndrome, and fascia pain of the temporal mandible.

  Particularly in the treatment of pain, it is useful to combine a Nav1.7 inhibitor with another pharmacologically active compound or two or more other pharmacologically active compounds. Such a combination offers significant potential benefits including patient compliance, ease of administration and synergistic activity.

In the following combinations, the compounds of the invention may be administered simultaneously, sequentially or separately with one or more other therapeutic agents.
A Nav1.7 inhibitor of formula (I) as defined above or a pharmaceutically acceptable salt thereof may be administered in combination with one or more agents selected from:
Other Nav1.7 channel modulators such as another compound of the invention or a compound disclosed in WO2009 / 012242,
A Nav1.3 modulator (eg as disclosed in WO 2008/118758) or a Nav1.8 modulator (eg as disclosed in WO 2008/135826), More particularly, other sodium channel modulations such as N- [6-amino-5- (2-chloro-5-methoxyphenyl) pyridin-2-yl] -1-methyl-1H-pyrazole-5-carboxamide) Agent,
Nerve growth factor signaling such as an agent that binds to NGF and inhibits one or more downstream pathways mediated by NGF biological activity and / or NGF signaling (eg, tanezumab), a TrkA antagonist or a p75 antagonist Inhibitors,
Compounds having fatty acid amide hydrolase (FAAH) inhibitory activity, particularly those disclosed in WO 2008/047229 (for example, N-pyridazin-3-yl-4- (3-{[5- Compounds that increase the concentration of endogenous cannabinoids such as (trifluoromethyl) pyridin-2-yl] oxy} benzylidene) piperidine-1-carboxamide),
Morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalolphine, naloxone, naltrexone, buprenorphine, butorphanol cine Opioid analgesics,
・ Aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbipro Non-steroidal anti-inflammatory drugs (NSAIDs) such as phen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetine or zomepirac,
・ Barbitur sedatives such as amobarbital, aprobarbital, butabarbital, butarbital, mehobarbital, metalbital, methohexital, pentobarbital, phenobarbital, secobarbital, tarbutal, thiamylal or thiopental,
Benzodiazepines with sedative activity such as chlordiazepoxide, chlorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam,
An H1 antagonist having a sedative action such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclidine,
Sedatives such as glutethimide, meprobamate, methacarone or dichlorarphenazone,
Skeletal muscle relaxants such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, metcarbamol or orphenadrine,
Dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinone, Cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, combined morphine and dextromethorphan), topiramate, neramexane or perzine hotel (ifenprodil, traxoprodil or (- )-(R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1-piperidinyl] -1-hydroxyethyl-3,4-dihydro-2 (1H) -quinolinone) NMDA receptors, including NR2B antagonists) Anti-drug,
Doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil or 4-amino-6,7-dimethoxy-2- (5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) Α-adrenergic agonists such as -5- (2-pyridyl) quinazoline,
・ Tricyclic antidepressants such as desipramine, imipramine, amitriptyline or nortriptyline,
Anticonvulsants such as carbamazepine, lamotrigine, topiramate or valproic acid,
(ΑR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9,10,11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1 , 4] diazocino [2,1-g] [1,7] -naphthyridine-6-13-dione (TAK-637), 5-[[(2R, 3S) -2-[(1R) -1- [ 3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] -methyl] -1,2-dihydro-3H-1,2,4-triazol-3-one Tachykinins (NK) such as (MK-869), aprepitant, ranepitant, dapitant or 3-[[2-methoxy-5- (trifluoromethoxy) phenyl] -methylamino] -2-phenylpiperidine (2S, 3S) Anti drugs, in particular, NK-3, NK-2 or NK-1 antagonists,
Muscarinic antagonists such as oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine and ipratropium,
A COX-2 selective inhibitor such as, for example, celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoroxixib or luminacoxib,
Coal tar analgesics, especially paracetamol,
Dropperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, bronanserin, iloperidone, perospirone, laclopridone , Bifeprunox, asenapine, lurasidone, amisulpiride, balaperidone, palindole, eprivanserin, osanetant, rimonabant, meclinertant (Miraxion: registered nerve)
A vanilloid receptor agonist (eg, resiniferatoxin) or an antagonist (eg, capsazepine),
Β-adrenergic drugs such as propranolol,
・ Local anesthetics such as mexiletine,
Corticosteroids such as dexamethasone,
-5-HT receptor agonists or antagonists, in particular 5-HT _{1B / 1D} agonists such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan,
-5-HT _2A receptor antagonism such as R (+)-α- (2,3-dimethoxy-phenyl) -1- [2- (4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907) medicine,
5-HT ₃ antagonists such as ondansetronIspronicline (TC-1734), (E) -N-methyl-4- (3-pyridinyl) -3-buten-1-amine (RJR-2403), R) -5- (2-azetidinylmethoxy) -2-chloropyridine (ABT-594) or cholinergic (nicotinic) analgesics such as nicotine,
・ Tramadol (registered trademark),
5- [2-Ethoxy-5- (4-methyl-1-piperazinyl-sulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] Pyrimidin-7-one (sildenafil), (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) -pyrazino [2 ′ , 1 ′: 6,1] -pyrido [3,4-b] indole-1,4-dione (IC-351 or tadalafil), 2- [2-ethoxy-5- (4-ethyl-piperazine-1- Yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one (Vardenafil), 5- (5-acetyl) -2-butoxy-3-pi Dinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- (5-acetyl-2-) Propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- [2- Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl) amino] -2-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -N- (pyrimidine-2- Ylmethyl) pyrimidine 5-carboxamide, 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- [2- (1- PDEV inhibitors such as methylpyrrolidin-2-yl) ethyl] -4-propoxybenzenesulfonamide,
Gabapentin, pregabalin, 3-methylgabapentine, (1α, 3α, 5α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, (3S, 5R) -3- Aminomethyl-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-octanoic acid, (2S, 4S)- 4- (3-Chlorophenoxy) proline, (2S, 4S) -4- (3-fluorobenzyl) -proline, [(1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] Hept-6-yl] acetic acid, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one, C- [1- (1H-tetrazol-5-ylmethyl) ) -Cycloheptyl Methylamine, (3S, 4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid, (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid, (3S, 5R) -3-amino-5-methyl-nonanoic acid, (3S, 5R) -3-amino-5-methyl-octanoic acid, (3R, 4R, 5R) -3-amino-4,5-dimethyl-heptanoic acid and Α-2-δ ligands such as (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid,
-Metabotropic glutamate receptor type 1 (mGluR1) antagonist,
Sertraline, sertraline metabolite demethyl sertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethyl citalopram, esitalopram, d, l-fenfluramine, femoxetine, ifoxetine Serotonin reuptake inhibitors such as cyanodothiepine, ritoxetine, dapoxetine, nefazodone, cericlamin and trazodone,
Noradrenaline (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolites hydroxybuproprion, nomifensine and viloxazine (Vivalan®), Selective noradrenaline reuptake inhibitors such as reboxetine (especially (S, S) -reboxetine),
Serotonin and noradrenaline double reuptake inhibitors such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolites desmethylclomipramine, duloxetine, milnacipran and imipramine,
S- [2-[(1-Iminoethyl) amino] ethyl] -L-homocysteine, S- [2-[(1-Iminoethyl) -amino] ethyl] -4,4-dioxo-L-cysteine, S -[2-[(1-Iminoethyl) amino] ethyl] -2-methyl-L-cysteine, (2S, 5Z) -2-amino-2-methyl-7-[(1-iminoethyl) amino] -5 Heptenoic acid, 2-[[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) -butyl] thio] -5-chloro-3-pyridinecarbonitrile, 2-[[(1R , 3S) -3-Amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -4-chlorobenzonitrile, (2S, 4R) -2-amino-4-[[2-chloro-5- (Trifluoromethyl) phenyl] thio] 5-thiazolebutanol, 2-[[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -6- (trifluoromethyl) -3-pyridinecarbonitrile, 2 -[[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -5-chlorobenzonitrile, N- [4- [2- (3-chlorobenzylamino) Inducible nitric oxide synthase (iNOS) inhibitors such as ethyl] phenyl] thiophene-2-carboxamidine or guanidinoethyl disulfide,
Acetylcholinesterase inhibitors such as donepezil,
N-[({2- [4- (2-Ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl] ethyl} amino) -carbonyl] -4- Prostaglandin E ₂ such as methylbenzenesulfonamide or 4-[(1S) -1-({[5-chloro-2- (3-fluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid Type 4 (EP4) antagonist,
A microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitor,
1- (3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) -cyclopentanecarboxylic acid (CP-105696), 5- [2- (2-carboxyethyl) -3- [6- Leukotriene B4 antagonists such as (4-methoxyphenyl) -5E-hexenyl] oxyphenoxy] -valeric acid (ONO-4057) or DPC-11870,
5-lipoxygenase inhibitors such as zileuton, 6-[(3-fluoro-5- [4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl]) phenoxy-methyl]- 1-methyl-2-quinolone (ZD-2138) or 2,3,5-trimethyl-6- (3-pyridylmethyl) 1,4-benzoquinone (CV-6504).

  Combinations of a compound of the present invention and one or more additional therapeutic agents that reduce the metabolic rate of the compound of the present invention and thereby increase patient exposure are also within the scope of the present invention. Such increased exposure is known as “boosting”. This has the advantage of increasing the effectiveness of the compounds of the present invention or reducing the dose required to achieve the same effectiveness as a dose not enhanced by adjuvants. Metabolism of the compounds of the present invention includes the oxidation process performed by P450 (CYP450) enzymes, particularly CYP3A4, and conjugation by UDP glucuronosyltransferases and sulfidases. Thus, one that can act as an inhibitor of at least one isoform of the cytochrome P450 (CYP450) enzyme is one of the agents that can be used with the compounds of the invention to increase patient exposure. It is. Isoforms of CYP450 that can be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitable agents that can be used to inhibit CYP3A4 include ritonavir, saquinavir, ketoconazole, N- (3,4-difluorobenzyl) -N-methyl-2-{[(4-methoxypyridine-3- Yl) amino] sulfonyl} benzamide and N- (1- (2- (5- (4-fluorobenzyl) -3- (pyridin-4-yl) -1H-pyrazol-1-yl) acetyl) piperidine-4- Yl) methanesulfonamide.

  It is within the scope of the invention to combine two or more pharmaceutical compositions, at least one of which contains a compound of the invention, conveniently in the form of a kit suitable for co-administration of the composition. Accordingly, the kit of the present invention separately comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention, and the composition, such as a container, a divided bottle, or a divided foil packet. Holding means. An example of such a kit is the well-known blister package used to package tablets and capsules and the like. The kit of the present invention administers different dosage forms (eg, oral and parenteral dosage forms), administers separate compositions at different dosing intervals, or doses separate compositions relative to each other. Especially suitable for. To assist in compliance, the kit typically includes directions for administration and may be provided with so-called memory aids.

  In another aspect, the invention provides a compound of the invention together with one or more additional therapeutically active agents as a combined formulation for simultaneous, separate or sequential use in the treatment of disorders where a Nav1.7 inhibitor is required. A pharmaceutical product (such as a kit form) is provided.

It is to be understood that all references herein include curative treatment, palliative treatment and prophylactic treatment.
In the non-limiting examples and preparations described later in this specification, and in the above scheme, the following abbreviations, definitions and analytical procedures are as follows:
AcOH is acetic acid,
Cs ₂ CO ₃ is cesium carbonate,
Cu (acac) ₂ is copper (II) acetylacetonate,
CuI is copper (I) iodide,
Cu (OAc) ₂ is copper (II) acetate,
DAD is a diode array detector,
DCM is dichloromethane, methylene chloride,
DIPEA is N-ethyldiisopropylamine, N, N-diisopropylethylamine,
DMAP is 4-dimethylaminopyridine,
DMF is N, N-dimethylformamide;
DMSO is dimethyl sulfoxide,
EDCI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride,
EDTA is ethylenediaminetetraacetic acid,
ELSD is evaporative light scattering detection,
Et ₂ O is diethyl ether,
EtOAc is ethyl acetate,
EtOH is ethanol,
HCl is hydrochloric acid,
IPA is isopropyl alcohol,
Ir ₂ (OMe) ₂ COD ₂ is bis (1,5-cyclooctadiene) di-μ-methoxydiiridium (I),
K ₂ CO ₃ is potassium carbonate,
KHSO ₄ is potassium hydrogen sulfate,
KOAc is potassium acetate;
KOH is potassium hydroxide,
K ₃ PO ₄ is tribasic potassium phosphate;
LCMS is liquid chromatography mass spectrometry (R _t = retention time)
LiOH is lithium hydroxide,
MeOH is methanol,
MgSO ₄ is magnesium sulfate,
NaH is sodium hydride,
NaHCO ₃ is sodium bicarbonate,
Na ₂ CO ₃ is sodium carbonate,
NaHSO ₃ is sodium bisulfate,
NaHSO ₄ is sodium hydrogen sulfate,
NaOH is sodium hydroxide,
Na ₂ SO ₄ is sodium sulfate,
NH ₄ Cl is ammonium chloride;
NMP is N-methyl-2-pyrrolidone;
Pd / C is palladium carbon,
Pd (PPh ₃ ) ₄ is palladium tetrakis,
Pd (dppf) ₂ Cl ₂ is a complex with [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), dichloromethane;
TBME is tert-butyl methyl ether,
THF is tetrahydrofuran,
THP is tetrahydropyran;
TLC is thin layer chromatography,
WSCDI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.

¹ H nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structure. Characteristic chemical shifts (δ) are conventional abbreviations for representing major peaks (eg, s: singlet, d: doublet, t: triplet, q: quadruple, m: multiplet. , Br: wide), and is expressed in ppm (parts per million) from tetramethylsilane to the low magnetic field side. For common solvents, the following abbreviations: CDCl _3: deuterated _chloroform, d 6-DMSO: deuterated dimethyl sulfoxide, and _CD 3 OD: using deuterated methanol.

Mass spectra or MS (m / z) were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Unless relevant and unless otherwise specified, the provided m / z data is for isotopes ¹⁹ F, ³⁵ Cl and ⁷⁹ Br.

Automated preparative high performance liquid chromatography (Auto-HPLC)
Certain compounds of the Examples and Preparations were purified using automated preparative high performance liquid chromatography (HPLC). Reverse phase HPLC conditions were either a FractionLynx system or a Tritulation system.

  For the Fractionlynx system, the sample was dissolved in 1 mL DMSO. Purification was carried out under acidic ("A-HPLC") or basic ("B-HPLC") conditions and ambient temperature, depending on the nature of the compound and the results of prior analysis. A-HPLC was performed on a Sunfire Prep C18 OBD column (19 × 100 mm, 5 μm), and B-HPLC was performed on an Xterra Prep MS C18 (19 × 100 mm, 5 μm). Both were manufactured by Waters. Mobile phase A: water + 0.1% modifier (v / v) and B: acetonitrile + 0.1% modifier (v / v) were used at a flow rate of 18 mL / min. In acidic experiments, the modifier was formic acid, and in basic experiments, the modifier was diethylamine. A Mobiles 2525 binary LC pump fed a mobile phase of 5% B composition for 1 minute, followed by 5% to 98% B for 6 minutes and maintained at 98% B for 2 minutes.

Detection was achieved using a Waters 2487 dual-wavelength absorbance detector set at 225 nm and then using a Polymer Labs PL-ELS 2100 detector and a Waters ZQ 2000 4-way MUX mass spectrometer simultaneously in succession. The PL 2100 ELSD was set at 30 ° C. and 1.6 L / min nitrogen supply. The Waters ZQ MS was adjusted to have the following parameters:
ES + cone voltage: 30v Capillary: 3.20kv
ES-cone voltage: -30 v Capillary: -3.00 kv
Desolvation gas: 600 L / hour Ion source temperature: 120 ° C.
Scanning range: 150 to 900 Da
Fraction collection was triggered by both MS and ELSD.

Quality control (QC) analysis was performed using the LCMS method. Acidity experiments were performed with Sunfire C18 (4.6 × 50 mm, 5 μm), and basic experiments were performed with Xterra C18 (4.6 × 50 mm, 5 μm). Both were manufactured by Waters. Mobile phase A: water + 0.1% modifier (v / v) and B: acetonitrile + 0.1% modifier (v / v) were used at a flow rate of 1.5 mL / min. In acidic experiments, the modifier was formic acid, and in basic experiments, the modifier was ammonia. Gradient elution from 5% to 95% B was performed for 3 minutes with a Waters 1525 binary LC pump and then maintained at 95% B for 1 minute. Detection was achieved using a Waters MUX UV 2488 detector set at 225 nm, and then successively using a Polymer Labs PL-ELS 2100 detector and a Waters ZQ 2000 4 way MUX mass spectrometer simultaneously. The PL 2100 ELSD was set at 30 ° C. and 1.6 L / min nitrogen supply. The Waters ZQ MS was adjusted to have the following parameters:
ES + cone voltage: 25v Capillary: 3.30kv
ES-cone voltage: -30 v Capillary: -2.50 kv
Desolvation gas: 800 L / hour Ion source temperature: 150 ° C.
Scanning range: 160 to 900 Da
The conditions were as follows when using a reverse phase Trition system (T-HPLC):
Mobile phase A: aqueous solution of 0.1% formic acid Mobile phase B: acetonitrile solution of 0.1% formic acid Column: Phenomenex C18 Luna (21.5 mm × 15 cm, particle size: 5 microns)
Gradient: 95-5% A for 15 minutes, 15 minutes maintenance, 15 mL / min flow rate UV: 200 nm-400 nm
Temperature: Room temperature Liquid Chromatography Mass Spectrometry When the above-described Auto-HPLC (A-HPLC or B-HPLC conditions) is not performed, or when not specifically performed as specifically described in the following Examples and Preparation Examples LCMS measurements were performed according to one of the following conditions (where solvent ratios are given, the ratio is based on volume).
Acidic 2 min LCMS
Mobile phase A: aqueous solution of 0.1% formic acid Mobile phase B: 70% methanol solution of 0.1% formic acid / 30% 2-propanol
Column: C18 phase Phenomenex (20 × 4.0 mm, particle size: 3 microns)
Gradient: 98-10% A for 1.5 min, 0.3 min maintenance, 0.2 re-equilibration, 2 mL / min flow rate UV: 210 nm to 450 nm DAD
Temperature: 75 ° C
Alternatively, mobile phase A: 0.1% formic acid in aqueous solution Mobile phase B: 0.1% formic acid in acetonitrile solution Column: C18 phase Phenomenex (20 × 4.0 mm, particle size: 3 microns)
Gradient: 70-2% A for 1.5 min, 0.3 min maintenance, 0.2 min re-equilibration, 1.8 mL / min flow rate UV: 210 nm to 450 nm DAD
Temperature: 75 ° C
Acidic 4.5 min LCMS
Mobile phase A: 0.05% formic acid in aqueous solution Mobile phase B: Acetonitrile column: Phenomenex Gemini C18 (45 × 45 mm, particle size: 5 microns)
Gradient: 80-50% A for 0.5 min, 50-2% A for 3 min, 1 min hold, 0.2 min re-equilibration, 2.0 mL / min flow rate UV: DAD from 220 nm to 254 nm
Temperature: 40 ° C
Acidic 8 min LCMS
Mobile phase A: 0.05% formic acid in aqueous solution Mobile phase B: Acetonitrile column: Phenomenex Gemini C18 (45 × 45 mm, particle size: 5 microns)
Gradient: 80-50% A for 0.5 min, 50-2% A for 3 min, 4.5 min maintenance, 0.2 min re-equilibration, 2.0 mL / min flow rate UV: 220 nm-254 nm DAD
Temperature: 40 ° C
Acidic 6 min LCMS
Mobile phase A: 0.1% formic acid in aqueous solution Mobile phase B: 0.1% formic acid in acetonitrile solution Column: C18 phase Waters Sunfire (50 × 4.6 mm, particle size: 5 microns)
Gradient: 95-5% A for 3 min, 1 min, 2 min re-equilibration, 1.5 mL / min flow rate UV: 210 nm to 450 nm DAD
Temperature: 50 ° C
Basic 6 minute LCMS
Mobile phase A: aqueous solution of 0.1% ammonium hydroxide Mobile phase B: acetonitrile solution of 0.1% ammonium hydroxide Column: C18 phase Fortis (50 × 4.6 mm, particle size: 5 microns)
Gradient: 95-5% A for 3 minutes, 1 minute maintenance, 2 minutes re-equilibration, 1 mL / min flow rate UV: 210 nm to 450 nm DAD
Temperature: 50 ° C
Acidic 30 min LCMS
Mobile phase A: 0.1% formic acid in aqueous solution Mobile phase B: 0.1% formic acid in acetonitrile solution Column: Phenomenex C18 phase Gemini (150 × 4.6 mm, particle size: 5 microns)
Gradient: 98-2% A for 18 min, 2 min maintenance, 1 mL / min flow rate UV: 210 nm to 450 nm DAD
Temperature: 50 ° C
Basic 30 minute LCMS
Mobile phase A: aqueous solution of 10 mM ammonium acetate Mobile phase B: methanol solution of 10 mM ammonium acetate Column: Phenomenex Phenyl Hexyl (150 × 4.6 mm, particle size: 5 microns)
Gradient: 98-2% A for 18 min, 2 min maintenance, 1 mL / min flow rate UV: 210 nm to 450 nm DAD
Temperature: 50 ° C
In the tabular experimental details below, the Examples and Preparative Examples compounds were prepared according to the corresponding reference methods (ie, Method A, Method B, Preparative Example 15, etc.). One skilled in the art will recognize that it may be desirable to slightly alter the reaction conditions of the reference method (eg, with respect to solvent and temperature, etc.) in the synthesis of the compounds of any specific example or preparation. There will be.

Example 1
4-[(5-Chloro-6-isobutoxypyridin-3-yl) oxy] -3-cyano-N- (methylsulfonyl) benzamide

Method A
4-[(5-Chloro-6-isobutoxypyridin-3-yl) oxy] -3-cyanobenzoic acid (Preparation Example 1, 0.17 g, 0.49 mmol), methanesulfonamide (0.093 g,. 98 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.175 mL, 1.0 mmol) were suspended in dichloromethane (3.0 mL). Subsequently, hexafluorophosphate N-[(dimethylamino) (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene] -N-methylmethanaminium (0.195 g 0.51 mmol) and the mixture was stirred in nitrogen at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (15.0 mL) and washed twice with aqueous hydrochloric acid (2.0 M, 10.0 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. After dissolving the crude residue in EtOAc (1.0 mL), heptane (10.0 mL) was slowly added until a solid was formed. The solid was collected by filtration and then further purified by silica gel column chromatography (ISCO®, gradient: 0-50% EtOAc / heptane, 12 g) to give the title compound as a white solid (0.038 g , 18%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 0.98 (s, 3H), 1.00 (s, 3H), 2.04-2.09 (m, 1H), 3.35 (s, 3H), 4.12 (d, 2H) , 7.07 (d, 1H), 8.10-8.13 (m, 2H), 8.18 (d, 1H), 8.45 (d, 1H).
LCMS Rt = 1.93 min, MS m / z 424 [MH] ⁺ .

Example 2
4-({5-Chloro-6-[(3,3-difluorocyclobutyl) methoxy] pyridin-3-yl} oxy) -2,5-difluoro-N- (methylsulfonyl) benzamide

Method B
4-({5-Chloro-6-[(3,3-difluorocyclobutyl) methoxy] pyridin-3-yl} oxy) -2,5-difluorobenzoic acid (Preparation Example 8, 0.155 g, 0.38 mmol) ), N- [3- (dimethylamino) propyl] -N′-ethylcarbodiimide hydrochloride (0.110 g, 0.57 mmol), DMAP (0.070 g, 0.57 mmol) and N-ethyl-N-isopropylpropane. 2-Amine (0.243 mL, 1.4 mmol) was dissolved in dichloromethane (10.0 mL). Methanesulfonamide (0.054 g, 0.57 mmol) was then added and the mixture was stirred at room temperature for 16 hours under nitrogen. The solvent was removed in vacuo. The residue was purified by reverse phase preparative HPLC (Trilution method) to give the title compound (0.073 g, 43%).
¹ H NMR (400 MHz, d ₆ -DMSO): δ 2.40-2.60 (m, 2H), 2.60-2.80 (m, 3H), 3.30 (s, 3H), 4.40 (m, 2H), 7.15 (m, 1H), 7.75 (m, 1H), 8.00 (s, 1H), 8.10 (s, 1H)
LCMS Rt = 4.36 min, MS m / z 481 [M] ^- .

Example 3
4-[(5-Chloro-6-isopropoxypyridin-3-yl) oxy] -2,5-difluoro-N- (methylsulfonyl) benzamide

Method C
To a solution of methanesulfonamide (441 mg, 4.64 mmol) in anhydrous tetrahydrofuran (18 mL) was added sodium hydride (60% oil dispersion, 186 mg, 4.64 mmol) and 4-[(5-chloro-6-isopropoxypyridine- 3-yl) oxy] -2,5-difluorobenzoic acid 4-methylphenyl (Preparation Example 9, 1.006 g, 2.32 mmol) was added. The reaction mixture was heated to 65 ° C. and stirred for 16 hours. After the reaction was cooled to 0 ° C., 1M aqueous solution of hydrogen chloride (20 mL) and EtOAc (20 mL) was added. The organics were separated, dried over sodium sulfate and concentrated in vacuo until a colorless solid. The crude material was dissolved in dichloromethane (10 mL), washed with water (2 × 5 mL) and dried over sodium sulfate. The organics were concentrated in vacuo to give a colorless solid which was slurried with 9: 1 heptane / acetone (14 mL). The solid was filtered, washed with cold eluent (9: 1 heptane / acetone, 10 mL) and dried to give the title compound as a colorless solid (792 mg):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.42-1.43 (d, 6H), 3.44 (s, 3H), 5.30-3.39 (m, 1H), 6.63-6.68 (m, 1H), 7.48-7.49 ( d, 1H), 7.92-7.97 (m, 2H), 8.70-8.73 (d, 1H).
LCMS Rt = 1.58 min, MS m / z 421 [MH] ⁺ , 419 [MH] ^- .

Example 4
3-Chloro-N- (methylsulfonyl) -4-[(2-piperidin-1-ylpyrimidin-5-yl) oxy] benzamide

Methyl 3-chloro-4-fluorobenzoate (23.6 mg, 0.125 mmol) and 2-piperidin-1-ylpyrimidin-5-ol (Preparative Example 10, 22.4 mg, 0.125 mmol) in pyridine (0. To the 5 mL) solution, cesium carbonate (122 mg, 0.375 mmol) and copper powder (16 mg, 0.25 mmol) were added and the reaction mixture was shaken at 120 ° C. for 16 hours. The reaction mixture was filtered and evaporated in vacuo. Water (1 mL) was added and the mixture was extracted with EtOAc (3 × 1 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was dissolved in tetrahydrofuran (0.7 mL), aqueous lithium hydroxide (0.7 mL of 1 M solution, 0.7 mmol) was added, and the reaction was shaken at 30 ° C. for 16 hours. The reaction was evaporated in vacuo and 1M aqueous hydrochloric acid (0.7 mL) was added. The mixture was extracted 3 times with EtOAc (3 × 1 mL) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue, methanesulfonamide (11.9 mg, 0.125 mmol), DMAP (45.8 mg, 0.375 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (55 mg, 0 .28 mmol) was dissolved in dichloromethane (1 mL), shaken at 30 ° C. for 16 hours and then evaporated in vacuo. The residue was purified by HPLC column (YMC-pack ODS-AQ (150 × 30 mm × 5 μm), acetonitrile-water (0.1% trifluoroacetic acid) gradient) to give the title compound (5.23 mg, 12.7 μmol).
LCMS Rt = 3.331 min, MS m / z 411 [MH] ⁺
LCMS conditions

Example 5
5-Chloro-2-fluoro-N- (methylsulfonyl) -4- (quinolin-3-yloxy) benzamide

  To a solution of quinolin-3-ol (18.1 mg, 0.125 mmol) and methyl 5-chloro-2,4-difluorobenzoate (Preparation Example 11, 25.9 mg, 0.125 mmol) in pyridine (0.5 mL), Cesium carbonate (82 mg, 0.25 mmol) and 16 mg (0.25 mmol) of copper powder (16 mg, 0.25 mmol) were added and the resulting mixture was shaken at 120 ° C. for 16 hours. After cooling, the mixture was filtered and evaporated in vacuo. Water (1 mL) was added and the mixture was extracted 3 times with EtOAc (3 × 1 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo.

  To a solution of this residue in THF (0.7 mL) was added 1M aqueous lithium hydroxide solution (0.7 mL) and the mixture was shaken at 30 ° C. for 16 hours. The reaction mixture was evaporated in vacuo, 1M aqueous hydrochloric acid (0.7 mL) was added and extracted with EtOAc (3 × 1 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo.

To this residue was added methanesulfonamide (28.6 mg, 0.300 mmol) and a solution of DMAP (24.4 mg, 0.200 mmol) and EDCI (38.3 mg, 0.200 mmol) in dichloromethane (1 mL). The solution was shaken at 30 ° C. for 16 hours and evaporated in vacuo. The resulting residue was purified by HPLC column (Sepax BR-C18 (100 × 21.2 mm × 5 μm, acetonitrile-water (0.1% trifluoroacetic acid) gradient) to give the title compound (3.81 mg 7.50 μmol).
LCMS Rt = 2.099min, MS m / z 393 [MH] ^-
LCMS method

Example 6
2,5-Difluoro-N- (methylsulfonyl) -4-[(6-nitropyridin-3-yl) oxy] benzamide

Potassium carbonate (0.220 g, 1.59 mmol) was added to 2,5-difluoro-4-hydroxy-N- (methylsulfonyl) benzamide (Preparation 34, 0.200 g, 0.796 mmol) and 5-bromo-2- To a stirred solution of nitropyridine (0.170 g, 0.836 mmol) in DMSO (2.5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and then at 60 ° C. for 24 hours. The reaction mixture was partitioned between EtOAc and 2M aqueous HCl to ensure the aqueous layer was acidic. The organic layer was separated and further washed with citric acid, water and brine, then dried over magnesium sulfate, filtered, evaporated in vacuo and triturated with diethyl ether to give the title compound (0.180 g, 60% ):
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.28 (s, 3H), 6.90-6.98 (m, 1H) 7.45 (d, 1H) 7.62-7.70 (m, 1H) 8.25 (d, 1H) 8.30 (s , 1H)
MS m / z 372 [MH] ^- .

Example 7
5-chloro-4-{[5-chloro-6- (1-fluoro-1-methylethyl) pyridin-3-yl] oxy} -2-fluoro-N- (methylsulfonyl) benzamide

Method E
Potassium tert-butoxide (6.4 mg, 0.057 mmol) was added to a suspension of methanesulfonamide (5.4 mg, 0.057 mmol) in THF (1.0 mL) and the mixture was stirred at room temperature for 15 minutes. Next, 4-methylphenyl 5-chloro-4-{[5-chloro-6- (1-fluoro-1-methylethyl) pyridin-3-yl] oxy} -2-fluorobenzoate (Preparation Examples 36, 20) .8 mg, 0.046 mmol) was added and the mixture was stirred at 60 ° C. for 6 hours. Methanesulfonamide (2.7 mg, 0.029 mmol) and potassium tert-butoxide (3.2 mg, 0.029 mmol) were added and the mixture was stirred for another 2 hours. The reaction was left to stir at room temperature for 16 hours, then concentrated in vacuo and the residue was partitioned between DCM (15 mL) and 10% aqueous citric acid (15 mL). The organic layer was then washed with water (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a crude oil. This oil was triturated with heptane (10 mL) to give the title compound as a white solid (5.6 mg, 7%):
¹ H NMR (400 MHz; CD ₃ OD): δ 1.78-1.83 (d, 6H), 3.36 (s, 3H), 7.08-7.11 (d, 1H), 7.61 (d, 1H), 7.93-7.95 (d , 1H), 8.26-8.27 (d, 1H)
LCMS Rt = 1.70 min, MS m / z 439 [MH] ⁺ .

Example 8
5-chloro-4-[(5-cyano-6-isopropoxypyridin-3-yl) oxy] -2-fluoro-N- (methylsulfonyl) benzamide

Method F
Potassium carbonate (232 mg, 1.68 mmol) was added to 5-hydroxy-2-isopropoxynicotinonitrile (Preparation 76, 100 mg, 0.56 mmol) and 5-chloro-2,4-difluoro-N- (methylsulfonyl). Benzamide (Preparation 28, 150 mg, 0.56 mmol) in DMSO (7 mL) was added and the mixture was heated at 90 ° C. for 16 hours. The reaction was quenched in saturated aqueous ammonium chloride (15 mL) and extracted with DCM (3 × 30 mL). The combined organics were washed with brine (2 × 30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 0-5% MeOH / DCM to give the title compound as a white solid (29 mg, 12%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 1.37 (d, 6H), 5.34 (m, 1H), 7.14 (d, 1H), 7.93 (d, 1H), 8.31 (d, 1H), 8.43 (d, 1H), 12.30 (br, 1H). CH ₃ -SO ₂ superimposed on water in d ₆ -DMSO at 3.33 ppm.
LCMS Rt = 2.64 min, MS m / z 426 [MH] ^- .

Example 9
4-{[5-Chloro-6- (trifluoromethyl) pyridin-3-yl] oxy} -N- (methylsulfonyl) benzamide

Method G
Methanesulfonamide (8.4 mg, 0.088 mmol) and bis (tert-butylcarbonyloxy) iodobenzene (38.5 mg, 0.095 mmol) were dissolved in isopropyl acetate (2.50 mL). 4-{[5-Chloro-6- (trifluoromethyl) pyridin-3-yl] oxy} benzaldehyde (Preparation 33, 26.5 mg, 0.088 mmol) was added and the mixture was stirred for 5 minutes. (Bis [rhodium (α, α, α ′, α′-tetramethyl-1,3-benzenedipropionic acid)]) (Rh ₂ (esp) ₂ ) (4.5 mg, 0.006 mmol) is added, The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound, which was purified by A-HPLC:
LCMS Rt = 2.29 min, MS m / z 393 [MH] ^- , 395 [MH] ⁺ .

Example 10
5-Chloro-4-{[5-chloro-6- (oxetane-3-yloxy) pyridin-3-yl] oxy} -2-fluoro-N- (methylsulfonyl) benzamide

Method H
5-chloro-4-[(5-chloro-6-fluoropyridin-3-yl) oxy] -2-fluoro-N- (methylsulfonyl) benzamide (Example 19, 0.147 g, 0.37 mmol), oxetane -3-ol (0.082 g, 1.11 mmol) and Cs ₂ CO ₃ (0.362 g, 1.11 mmol) were suspended in DMSO (1.0 mL) in a sealed bottle and heated at 100 ° C. for 1 hour. did. The reaction was diluted with EtOAc (15 mL) and washed with 10% aqueous citric acid (10 mL) and water (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a solid (175 mg). This solid was triturated with heptane / acetone (9: 1) then TBME, DCM and MeOH to give the title compound as a white solid (19 mg, 11%). The filtrates were combined and concentrated in vacuo to give a crude solid that was purified by reverse phase chromatography (13 g C ₁₈ Redisep, copyright) eluting with 5-80% MeCN / water. Fractions were combined, diluted with EtOAc (300 mL) and washed with 10% aqueous citric acid (10 mL), water (2 × 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a crude solid (100 mg) that was triturated with MeOH (3 mL) to give the title compound as a white solid (45 mg, 27 %). The overall yield was 64 mg (38%):
LCMS Rt = 1.54 min, MS m / z 451 [MH] ^{+ 1} H NMR (400 MHz, CD ₃ OD): δ 3.35 (s, 3H), 4.73-4.77 (m, 2H), 5.00-5.03 (m, 2H), 5.64-5.70 (m, 1H), 6.83-6.86 (d, 1H), 7.76-7.77 (d, 1H), 7.89-7.91 (m, 2H).

Example 11
4-({5-Chloro-6- [isopropyl (methyl) amino] pyridin-3-yl} oxy) -2,5-difluoro-N- (methylsulfonyl) benzamide

Method I
Triethylamine (35 μL, 0.25 mmol) and isopropylmethylamine (15 μL, 0.14 mmol) were added to 4-[(5-chloro-6-fluoropyridin-3-yl) oxy] -2,5-difluoro-N— ( Methylsulfonyl) benzamide (Preparation 30, 0.040 g, 0.105 mmol) was added to a solution of DMSO (1.00 mL) and the mixture was stirred in a sealed bottle at 60 ° C. for 16 hours. Isopropylmethylamine (15 μL, 0.14 mmol) was added and the mixture was stirred at 70 ° C. for 16 hours. Additional isopropylmethylamine (15 μL, 0.14 mmol) was added and the mixture was stirred at 70 ° C. for 16 hours. The reaction mixture was then partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. This was purified by reverse phase chromatography (13 g C18 Redisep (copyright)) eluting with 5-70% MeCN / water to give a white solid (250 mg) which was suspended in water and sonicated for 10 min. Work-up and filtration gave the title compound as a white solid (7.0 mg, 15%):
¹ H NMR (400 MHz; d ⁶ -DMSO): δ 1.12-1.14 (d, 6H), 2.71 (s, 3H), 3.34 (s, 3H), 3.98-4.05 (m, 1H), 7.10-7.15 ( q, 1H), 7.72-7.77 (q, 1H), 7.79-7.80 (d, 1H), 8.13-8.14 (d, 1H), 12.22 (br, 1H).
LCMS Rt = 1.60 min, MS m / z 434 [MH] ⁺ .

Example 12
4-{[5-Chloro-6- (2,2,2-trifluoro-1-methylethoxy) pyridin-3-yl] oxy} -2,5-difluoro-N- (methylsulfonyl) benzamide

Method J
NaH (0.023 g, 0.57 mmol) and 1,1,1-trifluoropropan-2-ol (0.03 mL, 0.29 mmol) were added to 4-[(5-chloro-6-fluoropyridine-3- Yl) oxy] -2,5-difluoro-N- (methylsulfonyl) benzamide (Preparation 30, 0.055 g, 0.14 mmol) was added to a THF solution and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (2 × 5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound:
LCMS Rt = 3.36 min, MS m / z 473 [MH] ^- .

Example 13
5-chloro-4-{[5-chloro-6- (3,3,3-trifluoropropoxy) pyridin-3-yl] oxy} -2-fluoro-N- (methylsulfonyl) benzamide

Method D
4-methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation Example 26, 150 mg, 0.53 mmol) was converted to 5-chloro-6- (3,3,3-trifluoropropoxy) pyridin-3-ol. (Preparation Example 95, 134 mg, 0.56 mmol) and K ₂ CO ₃ (147 mg, 1.06 mmol) in DMSO (5 mL) was added. The reaction mixture was stirred at room temperature for 1.5 hours. DBU (135 μL, 0.90 mmol) and methanesulfonamide (56 mg, 0.58 mmol) were then added to the reaction and heated at 50 ° C. for 2 hours. The reaction was quenched with water and extracted with EtOAc. The combined organics were dried and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography to give the title compound as a white solid (170 mg):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 2.80 (m, 2H), 3.40 (s, 3H), 4.60 (m, 2H), 7.10 (m, 1H), 7.95 (m, 1H), 8.00 (m, 1H), 8.15 (m, 1H).
LCMS Rt = 3.13 min, MS m / z 489 [MH] ^- .

Example 14
4-[(5-Chloro-6-isobutoxypyridin-3-yl) oxy] -N- (methylsulfonyl) benzamide

Method L
A solution of lithium bis (trimethylsilyl) amide in THF (0.66 mL, 0.66 mmol) was added to 4-[(5-chloro-6-isobutoxypyridin-3-yl) oxy] benzamide (Preparation Example 31, 0.090 g, 0.281 mmol) in THF (3 mL) was added at room temperature. After 30 minutes, methanesulfonyl chloride (0.052 mL, 0.672 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, dissolved in DMSO (1.5 mL) and reverse phase chromatography (26 g C18 Redisep, copyright) eluting with 5-95% MeCN (with 5% ammonia) / water. Purified. Fractions with product were combined and concentrated in vacuo. The residue was then partitioned between EtOAc (15 mL) and aqueous HCl (2M, 15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a solid (18.5 mg, 17%):
¹ H NMR (400 MHz; CD ₃ OD): δ 1.04 (s, 3H), 1.05 (s, 3H), 1.28 (t, 3H), 2.11 (m, 1H), 3.35 (s, 3H), 4.14 ( d, 2H), 7.05 (m, 1H), 7.64 (d, 1H), 7.90-7.93 (m, 3H).
LCMS Rt = 1.64 min, MS m / z 399 [MH] ⁺ .

Example 15
4- (5-Chloro-6-methoxypyridin-3-yloxy) -N- (cyclopropylsulfonyl) -2,5-difluorobenzamido diethylamine salt

Lithium salt of 4- (5-chloro-6-methoxypyridin-3-yloxy) -2,5-difluorobenzoic acid (Preparation Example 17, 59.2 mg, 0.176 mmol), hexafluorophosphoric acid N-[(dimethyl Amino) (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene] -N-methylmethanaminium (0.174 g, 0.458 mmol), N, N-diisopropyl A mixture of DCM (15 mL) and DMF (0.15 mL) containing ethylamine (418 μL, 2.40 mmol) and 4-dimethylaminopyridine (6.1 mg, 0.499 mmol) was stirred at room temperature for 15 minutes before cyclopropanesulfonamide. (282.2 mg, 2.33 mmol) was added. The reaction mixture was heated at 50 ° C. in a nitrogen atmosphere for 18 hours, cooled to room temperature, and concentrated in vacuo. The crude residue was partitioned between aqueous HCl (0.5 M, 15 mL) and DCM (30 mL). The organic layer was washed with aqueous HCl (0.5 M, 2 × 15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow solid (62 mg) which was purified by preparative B-HPLC. To give the title compound as a diethylamine salt.
LCMS Rt = 3.28 min, MS m / z 419 [MH] ⁺ .

Example 16
4- (5-Chloro-6-cyclobutoxypyridin-3-yloxy) -2,5-difluoro-N- (methylsulfonyl) benzamide

2,4,5-trifluoro-N- (methylsulfonyl) benzamide (Preparation Example 27, 0.317 g, 1.25 mmol), 5-chloro-6-cyclobutoxypyridin-3-ol (Preparation Example 19, 0. 250 g, 1.25 mmol) and potassium carbonate (0.346 g, 2.50 mmol) were suspended in DMSO (16 mL) and heated at 90 ° C. for 48 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 20% EtOAc (with 0.5% AcOH) / heptane to give the title compound as a white solid (64 mg, 12%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.71 (m, 1H), 1.89 (m, 1H), 2.24 (m, 2H), 2.50 (m, 2H), 3.43 (s, 3H), 5.23 (m , 1H), 6.65 (m, 1H), 7.47 (m, 1H), 7.90 (m, 1H), 7.93 (m, 1H), 8.70 (s, 1H).
LCMS Rt = 3.56 min, MS m / z 433 [MH] ⁺ .

Example 18
N- (sec-butylsulfonyl) -4-[(5-chloro-6-methoxypyridin-3-yl) oxy] -2,5-difluorobenzamide

Potassium carbonate (0.140 g, 1.01 mmol) was stirred in DMSO (1 mL) of N- (sec-butylsulfonyl) -2,4,5-trifluorobenzamide (Preparation Example 68, 0.090 g, 0.30 mmol). Added to the solution. After 10 minutes, a solution of 5-chloro-6-methoxypyridin-3-ol (Preparation 77, 0.088 g, 0.51 mmol) in DMSO (2 mL) was added at room temperature. The mixture was heated at 90 ° C. for 72 hours. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organics were washed with water (25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0-66% EtOAc / heptane to give the title compound (0.068 g):
¹ H NMR (400 MHz; CDCl ₃ solution): δ 0.90 (m, 1H), 1.30 (m, 1H), 1.50 (m, 1H), 1.90 (m, 1H), 2.00 (m, 1H), 4.00 ( s, 3H), 6.45 (m, 1H), 7.40 (s, 1H), 7.65 (m, 1H), 7.85 (s, 1H).
LCMS Rt = 3.46 min, MS m / z 435 [MH] ⁺ .

Example 19
5-Chloro-4-[(5-chloro-6-fluoropyridin-3-yl) oxy] -2-fluoro-N- (methylsulfonyl) benzamide

5-chloro-4- (5-chloro-6-fluoropyridin-3-yloxy) -2-fluorobenzoic acid (Preparation Example 162, 6.100 g, 19.60 mmol), 4-dimethylaminopyridine (2.330 g, 19.06 mmol), N- [3- (dimethylamino) propyl] -N′-ethylcarbodiimide hydrochloride (5.480 g, 28.59 mmol) and methanesulfonamide (2.720 g, 28.59 mmol) were added to DCM ( 20 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with 1M aqueous HCl and extracted with EtOAc. The combined organics were concentrated in vacuo. The resulting residue was purified by reverse phase chromatography to give the title compound as a white solid (4.50 g):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 3.40 (s, 3H), 3.10 (m, 1H), 7.95 (m, 1H), 8.20 (s, 1H), 8.30 (m, 1H).
LCMS Rt = 2.93 min, MS m / z 397 [MH] ⁺ .

Example 20
5-Chloro-2-fluoro-4-[(1-isopropyl-1H-indazol-5-yl) oxy] -N- (methylsulfonyl) benzamide

Sodium hydride (60% mineral oil solution, 0.012 g, 0.306 mmol) was added to 1-isopropyl-1H-indazol-5-ol (Preparation 39, 0.045 g, 0) while cooling the reaction in an ice bath. .225 mmol) in THF (3.0 mL) and stirred for 40 minutes. Then 5-chloro-2,4-difluoro-N (methylsulfonyl) benzamide (Preparation Example 28, 0.076 g, 0.28 mmol) was added and the reaction was heated at 60 ° C. for 16 hours. The reaction mixture was concentrated in vacuo and the residue was treated with EtOAc (25.0 mL) and washed with water (30.0 mL) then brine (30.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 2% methanol / DCM to afford the title compound as a white solid (8. 3 mg):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.62 (s, 3H), 1.64 (s, 3H), 3.40 (s, 3H), 4.91-4.97 (m, 1H), 6.53 (d, 1H), 7.10 (d, 1H), 7.53 (s, 1H), 7.60 (d, 1H), 8.02 (s, 1H), 8.32 (d. 1H), 10.03 (s, 1H).
LCMS Rt = 3.31 min, MS m / z 426 [MH] ⁺ .

Example 21
5-Chloro-4-[(5-chloro-6-cyclopropylpyridin-3-yl) oxy] -2-fluoro-N- (methanesulfonyl) benzamide

5-chloro-4-[(5-chloro-6-cyclopropylpyridin-3-yl) oxy] -2-fluorobenzoic acid 4-methylphenyl (Preparation Example 70, 0.285 g, 0.659 mmol) and methanesulfone The amide (0.069 g, 0.725 mmol) was suspended in acetonitrile (3.0 mL). 2,3,4,6,7,8,9,10-Octahydropyrimido [1,2-a] azepine (0.110 mL, 0.737 mmol) was added and the mixture was stirred at 50 ° C. for 16 hours. . The reaction mixture was concentrated in vacuo, diluted with DCM (15.0 mL), washed with water (15.0 mL), then 10% aqueous citric acid (15.0 mL), then water (2 × 15.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a solid which was triturated with a heptane / acetone mixture (9: 1, 10.0 mL) to give the title compound as a white solid. (0.208 g, 0.496 mmol, 75%):
LCMS Rt = 1.29 min, MS m / z 419 [MH] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 1.05-1.14 (m, 4H), 2.50-2.56 (m, 1H), 3.43 (s, 3H), 6.62 (d, 1H), 7.40 (d, 1H) , 8.20 (d, 1H), 8.23 (d, 1H), 8.65-8.69 (br, 1H).
The compound of Example 21 was prepared according to the following method.

To a solution of 5-chloro-4-[(5-chloro-6-cyclopropylpyridin-3-yl) oxy] -2-fluorobenzoic acid (Preparation Example 265, 45.0 g, 131.52 mmol) in tetrahydrofuran (180 mL). , Methanesulfonamide (25.02 g, 263.04 mmol), N-ethyl-N-diisopropylpropan-2-amine (68.81 mL, 394.56 mmol) and 1-propanephosphonic acid cyclic anhydride (167.36 g, 263 (.04 mmol, as a 50% ethyl acetate solution) was added at room temperature and the mixture was stirred and heated at 70-75 ° C. for 16 h. The reaction mixture was concentrated under reduced pressure at 45 ° C., water (450 mL) was added and the resulting slurry was stirred for 30 minutes, filtered and dried. The crude product was dissolved in 2-propanol (1285 mL) at 85 ° C. and cooled slowly over 16 hours. The resulting slurry was filtered, washed with 2-propanol (2 × 40 mL) and dried to give the title compound as an off-white solid (46 g, 83%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.05-1.17 (m, 4H), 2.54 (tt, 1H), 3.44 (s, 3H), 6.62 (d, 1H), 7.41 (d, 1H), 8.21 (d, 1H), 8.24 (d, 1H), 8.67 (br d, 1H)
HPLC Rt = 6.14 min.

Example 22
5-chloro-4-{[5-chloro-6- (2,2,3,3-tetrafluoropropoxy) pyridin-3-yl] oxy} -2-fluoro-N- (methanesulfonyl) benzamide

Methanesulfonamide (0.867 g, 9.12 mmol), N-ethyl-N-isopropylpropan-2-amine (2.40 mL, 13.8 mmol) and 2,4,6-tripropyl-1,3,5 A solution of 2,4,6-trioxatriphosphinane 2,4,6-trioxide in EtOAc (8.15 mL, 13.7 mmol) was added to 5-chloro-4-{[5-chloro-6- (1,1,1, 3,3-tetrafluoropropoxy) pyridin-3-yl] oxy} -2-fluorobenzoic acid (Preparation 72, 1.97 g, 4.56 mmol) was added to a solution of THF (40.0 mL) and the mixture was refluxed. Stirred under for 16 hours. The reaction mixture was concentrated in vacuo and then diluted with EtOAc (40.0 mL). The organics were washed with water (2 × 40.0 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a solid. The resulting solid was suspended in propan-2-ol (20.0 mL) and stirred at reflux until completely dissolved. The title compound was isolated by filtration after cooling as a pale yellow solid (1.62 g, 2.65 mmol, 58%):
LCMS Rt = 2.56min, MS m / z 509 [MH] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 3.42 (s, 3H), 4.76-4.83 (m, 2H), 5.93-6.22 (m, 1H), 6.60 (d, 1H), 7.55 (d, 1H) , 7.93 (d, 1H), 8.23 (d, 1H), 8.65-8.69 (br, 1H).
In addition, the compound of Example 22 was prepared according to the following method.
Method M
5-chloro-4-{[5-chloro-6- (1,1,3,3-tetrafluoropropoxy) pyridin-3-yl] oxy} -2-fluorobenzoic acid (Preparation Example 72, 30.2 g, 0.699 mmol) and methanesulfonamide (13.5 g, 0.142 mol) were dissolved in tetrahydrofuran (150 mL). Then N-ethyl-N-diisopropylpropan-2-amine (37 mL, 0.212 mol) and 1-propanephosphonic acid cyclic anhydride in ethyl acetate (50% wt solution, 120 mL, 0.200 mol) were added, The mixture was stirred at reflux for 18 hours. After cooling the reaction system to room temperature, the solution was concentrated in vacuo, the residue was suspended in water (150 mL), and extracted with ethyl acetate (150 mL). The organic layer was separated and washed with water (2 × 150 mL). The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo to give a beige solid. This solid was suspended in 2-propanol (375 mL), heated to 100 ° C. and stirred until a complete solution was observed. The solution was cooled to room temperature and the resulting solid was collected by filtration. The title compound was isolated as a pale yellow solid (30.98 g, 87%).
¹ H NMR (400 MHz; CDCl ₃ ): δ 3.45 (s, 3H), 4.82 (m, 2H), 5.96-6.25 (tt, 1H), 6.62 (d, 1H), 7.57 (d, 1H), 7.96 (d, 1H), 8.26 (d, 1H), 8.70 (br d, 1H)
HPLC Rt = 6.489 min.

  The following compounds were prepared by Method A as described above for Example 1 using appropriate preparations and conditions.

  The following compounds were prepared by Method B as described above for Example 2 using appropriate preparations and conditions.

  The following compounds were prepared by Method C as described above for Example 3 using the appropriate preparations and conditions.

  The following compounds were prepared by Method D as described above for Example 13 using the appropriate preparations and conditions.

  The following compounds were prepared by Method E as described above for Example 7 using the appropriate preparations and conditions.

  The following compounds were prepared by Method F as described above for Example 8 using the appropriate preparations and conditions.

  The following compounds were prepared by Method G as described above for Example 9 using the appropriate preparations and conditions.

  The following compounds were prepared by Method H as described above for Example 10 using the appropriate preparations and conditions.

  The following compounds were prepared by Method I as described above for Example 11 using the appropriate preparations and conditions.

  The following compounds were prepared by Method J as described above for Example 12 using the appropriate preparations and conditions.

  The following compounds were prepared by Method L as described above for Example 14 using the appropriate preparations and conditions.

Example 91
2,5-dichloro-4- (5-chloro-6-cyclopropylpyridin-3-yloxy) -N- (methylsulfonyl) benzamide

4-Dimethylaminopyridine (51 mg, 0.42 mmol) and N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol) were added to 2,5-dichloro-4- (5- Chloro-6-cyclopropylpyridin-3-yloxy) benzoic acid (Preparation Example 220, 100 mg, 0.28 mmol) was added to a suspension of dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 20 minutes. Methylsulfonamide (40 mg, 0.42 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours before being concentrated in vacuo. The crude compound was purified by reverse phase column chromatography eluting with acetonitrile: water (5:95 to 95: 5) followed by preparative HPLC to give the title compound (15.1 mg, 12%).
LCMS Rt = 3.72 min, MS m / z 435 [MH] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 1.05-1.12 (m, 4H), 2.48-2.55 (m, 1H), 3.41 (s, 3H), 6.87 (s, 1H), 7.35 (d, 1H) , 8.02 (s, 1H), 8.16 (d, 1H).

Example 92
5-Chloro-4- (5-chloro-6-cyclopropylpyridin-3-yloxy) -N- (cyclopropylsulfonyl) -2-fluorobenzamide

5-chloro-4- (5-chloro-6-cyclopropylpyridin-3-yloxy) -2-fluorobenzoic acid (Preparation Example 265, 15 mg, 0.44 mmol), 4-dimethylaminopyridine (81 mg, 0.66 mmol) ) And N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (127 mg, 0.66 mmol) were suspended in dichloromethane (2.5 mL). After the reaction mixture was stirred for 20 minutes, dimethylformamide (4 mL) was added and the suspension was stirred for 10 minutes. Cyclopropanesulfonamide (107 mg, 0.88 mmol) and N, N-diisopropylethylamine (160 μL, 0.88 mmol) were added and the reaction mixture was stirred at room temperature for 18 hours. The crude reaction mixture was semi-preparative reversed phase HPLC (column: Phenomenex Luna C18 (150 × 21.2 mm, 110A, 5μ), 2 ml injection, 254 nm detected, 5 ml fractions each, gradient solvent A: 0.05 % HCO ₂ H / acetonitrile, Solvent B: 0.05% HCO ₂ H / water, 10% A after 0 minutes, 10% A after 2.5 minutes, 95% A after 32.5 minutes, 37.5 minutes later Purification after 95% A, back to starting conditions, flow rate 15 ml / min) afforded the title compound as a white solid (43 mg, 22%).
LCMS Rt = 3.01min, MS m / z 445 [MH] ^+
1 H NMR (400MHz, CD ₃ OD): δ 1.05 (m, 4H), 1.14 (m, 2H), 1.29 (m, 2H), 2.54 (m, 1H), 3.10 (m, 1H), 6.93 (m , 1H), 7.58 (m, 1H), 7.89 (m, 1H), 8.18 (m, 1H).

Example 93
5-Chloro-4-((5-chloro-6-cyclopropylpyridin-3-yl) methyl) -2-fluoro-N- (methylsulfonyl) benzamide

To a solution of tetrahydrofuran (10 mL) and water (2 mL) was added 3-chloro-2-cyclopropyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine ( Preparative Example 221, 32 mg, 0.11 mmol), 4- (Bromomethyl) -5-chloro-2-fluoro-N- (methylsulfonyl) benzamide (Preparative Example 243, 43 mg, 0.13 mmol) and potassium carbonate (46 mg, 0 .35 mmol) was added. The flask was degassed with N ₂ (× 5) and tetrakistriphenylphosphine palladium (13.2 mg, 0.01 mmol) was added. The flask was degassed with N ₂ (× 5) and heated to 65 ° C. for 18 hours. The reaction system was allowed to cool to room temperature and washed with saturated aqueous ammonium chloride (100 mL). The reaction was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over MgSO ₄ , filtered and the solvent removed to give a yellow oil. This material was purified by silica gel column chromatography eluting with 1: 1 heptane: ethyl acetate to give the title compound as a yellow oil which solidified on standing to a pale yellow solid (23 mg, 48 %).
LCMS Rt = 2.82 min, MS m / z 417 [MH] ^+
1 HNMR (400 MHz, CDCl ₃ ): δ 0.98-1.10 (m, 4H), 2.42-2.52 (m, 1H), 3.40 (s, 3H), 4.03 (s, 2H), 6.96 (d, 1H), 7.36 (s, 1H), 8.08 (d, 1H), 8.19 (s, 1H).

Example 94
5-Chloro-4-[(5-chloro-6-isopropoxypyridin-3-yl) thio] -2-fluoro-N- (methylsulfonyl) benzamide

To a suspension of methanesulfonamide (93.4 mg, 0.98 mmol) in THF (2 mL), potassium tert-butoxide (119 mg, 1.06 mmol) was added in one portion at room temperature with stirring in nitrogen for 15 minutes. did. 5-methyl-4-[(5-chloro-6-isopropoxypyridin-3-yl) thio] -2-fluorobenzoate 4-methylphenyl (Preparation Example 224, 352 mg, 0.75 mmol) in THF (2 mL) ). The mixture was then heated at 60 ° C. for 3 hours and then left at room temperature for 18 hours. The solvent was concentrated in vacuo and the residue was partitioned between EtOAc (10 mL) and water (5 mL). After separation of the organic layer, it was washed with 1M NaOH (5 mL), 2M HCl (5 mL), saturated brine solution (5 mL), dried over MgSO ₄ , filtered and evaporated. The residue was triturated with acetone / heptane (1: 9) to give a white solid, which was filtered and washed with heptane to give the title compound (45 mg, 13%) as a white solid.
LCMS Rt = 2.97 min, MS m / z 451 [MH] ^-
1 HNMR (400 MHz, d ⁶ -DMSO): δ 1.45 (d, 6H), 3.40 (s, 3H), 5.40-5.46 (m, 1H), 6.43 (d, 1H), 7.77 (s, 1H), 8.08 (d, 1H), 8.20 (s, 1H), 8.55-8.70 (br s, 1H).

Example 95
5-Chloro-4- (5-chloro-6- (3,3-difluoropyrrolidin-1-yl) pyridin-3-yloxy) -2-fluoro-N- (methylsulfonyl) benzamide

Triethylamine (0.21 mL, 1.51 mmol) was added to 5-chloro-4- [5-chloro-6-fluoropyridin-3-yl) oxy] -2-fluoro-N- (methylsulfonyl) benzamide (Example 19). , 150 mg, 0.38 mmol) and 3,3-difluoropyrrolidine hydrochloride (60 mg, 0.41 mmol) in DMSO (3.8 mL) were added and the reaction was heated at 80 ° C. for 120 h. The mixture was diluted to 5 mL with the addition of water and the mixture was purified by preparative HPLC. The title compound was obtained as a beige solid (49 mg, 27%).
LCMS Rt = 3.69 min, MS m / z 484 [MH] ^+
1 HNMR (400 MHz, CDCl ₃ ): δ 2.43 (m, 2H), 3.40 (d, 3H), 3.91 (t, 2H), 4.06 (t, 2H), 6.57 (d, 1H), 7.39 (d, 1H), 7.99 (d, 1H), 8.20 (m, 1H).

Example 96
5-Chloro-4- (5-chloro-6- (3,3-difluoroazetidin-1-yl) pyridin-3-yloxy) -2-fluoro-N- (methylsulfonyl) benzamide

3,3-Difluoroazetidine hydrochloride (98 mg, 0.76 mmol) was added to 5-chloro-4- (5-chloro-6-fluoropyridin-3-yloxy) -2-fluoro-N- (methylsulfonyl) benzamide. (Example 19, 150 mg, 0.38 mmol) and potassium carbonate (74 mg, 0.53 mmol) were added to a suspension of dimethyl sulfoxide (1 mL). The reaction mixture was stirred at 90 ° C. in a microwave apparatus for 15 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude compound was purified by reverse phase preparative HPLC eluting with acetonitrile: water (5:95 to 95: 5) to give the title compound as a colorless solid (44 mg, 25%).
LCMS Rt = 3.61 min, MS m / z 470 [MH] ^+
1 H NMR (400 MHz, d ⁶ -DMSO): δ 3.27 (s, 3H), 4.53 (t, 4H), 6.91 (d, 1H), 7.83 (d, 1H), 7.89 (d, 1H), 8.11 (d, 1H).

Example 97
4-[(6-tert-Butoxy-5-chloropyridin-3-yl) methyl] -2,5-difluoro-N- (methylsulfonyl) benzamide

4- (Bromomethyl) -2,5-difluoro-N- (methylsulfonyl) benzamide (Preparation Example 245, 70 mg, 0.21 mmol), 2-tert-butoxy-3-chloro-5- (4,4,5,5) 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (Preparation Example 118, 72.9 mg, 0.234 mmol), tetrakistriphenylphosphine palladium (24.3 mg, 0.021 mmol), aqueous potassium carbonate solution (1.8M, 0.35 mL, 0.639 mmol) and tetrahydrofuran (15 mL) were combined and stirred under nitrogen for 5 hours under reflux. After cooling, the mixture was filtered through Celite ™ and the filtrate was evaporated. The residue was dissolved in water (20 mL), acidified with aqueous potassium hydrogen sulfate (0.5 M) to pH 2, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was separated, washed with brine (3 × 20 mL), dried over sodium sulfate, filtered and evaporated to give an oil. The oil was purified by silica gel column chromatography eluting with heptane-ethyl acetate: heptane 1: 1 to give a solid. This solid was further purified by reverse phase HPLC to give the title compound (21 mg, 23%) as a white solid.
LCMS Rt = 3.86 min, MS m / z 433 [MH] ⁺ .

Example 98
5-chloro-4-({5-chloro-6-[(1S) -2,2,2-trifluoro-1-methylethoxy] pyridin-3-yl} oxy) -2-fluoro-N- (methyl Sulfonyl) benzamide

To a solution of methanesulfonamide (26 mg, 0.28 mmol) in THF (2 mL) was added potassium tert-butoxide (32 mg, 0.28 mmol) and the mixture was stirred at room temperature for 10 minutes. 5-chloro-4-({5-chloro-6-[(1S) -2,2,2-trifluoro-1-methylethoxy] pyridin-3-yl} oxy) -2-methyl 4-fluorobenzoate Phenyl (Preparation 230, 108 mg, 0.21 mmol) in THF (2 mL) was added and the mixture was stirred at 50 ° C. for 10 hours. The reaction mixture was allowed to cool to room temperature. The reaction was quenched with water and acidified with 1N aqueous citric acid. The mixture was extracted with DCM (3 × 5 mL) and filtered using a phase separation cartridge. The filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography eluting with 0-100% EtOAc / heptane to give the product mixture as a white solid. The solid was purified by reverse phase column chromatography using a 5 to 95% CH 3 CN _/ water as an eluent to give a white solid which was further purified by trituration with heptane / acetone = 9/1 To give the title compound (28 mg, 27%) as a white solid.
¹ H NMR (400 MHz; d ⁶ -DMSO): δ 1.51 (d, 3H), 3.35 (s, 3H), 5.87 (m, 1H), 7.17 (d, 1H), 7.94 (d, 1H), 8.10 (d, 1H), 8.15 (d, 1H)
LCMS Rt = 2.80 min, MS m / z 491 [MH] ⁺ , 489 [MH] ^-
The compound of Example 98 was also prepared as follows:
Diisopropylethylamine (11.7 mL, 66.8 mmol) was added to (S) -5-chloro-4-((5-chloro-6-((1,1,1-trifluoropropan-2-yl) oxy) pyridine. -3-yl) oxy) -2-fluorobenzoic acid (Preparation Example 299, 6.9 g, 16.7 mmol), (2- (7-aza-1H-benzotriazol-1-yl) -1,1,3 , 3-tetramethyluronium hexafluorophosphate) (9.5 g, 25.1 mmol) and methylsulfonamide (2.4 g, 25.1 mmol) in dichloromethane (125 mL). The reaction mixture was stirred at room temperature for 20 hours and then quenched with aqueous hydrogen chloride (2M, 50 mL). The organics were removed in vacuo and the aqueous residue was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude compound is purified by silica gel chromatography using dichloromethane: methanol (100: 0 to 96: 4) as eluent, followed by reverse phase chromatography using acetonitrile: water (5:95 to 95: 5) as eluent. To give the title compound as a white solid (4.8 g, 56%).
LCMS Rt = 4.13min, m / z 491 [M + H] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 1.49 (d, 3H), 3.34 (s, 3H), 5.84 (m, 1H), 7.15 (d, 1H), 7.92 (d, 1H), 8.08 (d , 1H), 8.13 (d, 1H).
¹⁹ F NMR (400 MHz, CDCl ₃ ): δ -77, -110.

Example 99
5-chloro-4-({5-chloro-6-[(1R) -2,2,2-trifluoro-1-methylethoxy] pyridin-3-yl} oxy) -2-fluoro-N- (methyl Sulfonyl) benzamide

To a solution of methanesulfonamide (105 mg, 1.1 mmol) in THF (4 mL) was added potassium tert-butoxide (126 mg, 1.1 mmol) and the mixture was stirred at room temperature for 10 minutes. 5-chloro-4-({5-chloro-6-[(1R) -2,2,2-trifluoro-1-methylethoxy] pyridin-3-yl} oxy) -2-methyl 4-fluorobenzoate Phenyl (Preparation Example 234, 429 mg, 0.85 mmol) in THF (4 mL) was added and the resulting mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was allowed to cool to room temperature. The reaction was quenched with water and acidified with 1N aqueous citric acid. The mixture was partitioned between water and DCM (3 × 5 mL) and filtered through a phase separation cartridge. The filtrate was concentrated in vacuo to give a crude solid which was purified by trituration with heptane / acetone = 9/1 to give the title compound (199 mg, 48%) as a white solid.
¹ H NMR (400 MHz; d ⁶ -DMSO): δ 1.51 (d, 3H), 3.36 (s, 3H), 5.87 (m, 1H), 7.18 (d, 1H), 7.95 (d, 1H), 8.11 (d, 1H), 8.16 (d, 1H).
LCMS Rt = 2.80 min, MS m / z 491 [MH] ⁺ , 489 [MH] ^- .

Example 100
5-Chloro-4-[(5-chloro-6-phenoxypyridin-3-yl) oxy] -2-fluoro-N- (methylsulfonyl) benzamide

5-chloro-4-[(5-chloro-6-fluoropyridin-3-yl) oxy] -2-fluoro-N- (methylsulfonyl) benzamide (Example 19, 100 mg, 0.25 mmol) and phenol (71 mg , 0.76 mmol) in DMSO (1 mL) was added Cs ₂ CO ₃ (246 mg, 0.76 mmol) in N ₂ at room temperature. The resulting mixture was stirred at 100 ° C. for 45 minutes. The reaction mixture was allowed to cool to room temperature. The reaction was quenched with water and acidified with 1N aqueous citric acid. The mixture was extracted with DCM (3 × 3 mL) and filtered through a phase separation cartridge. The organic phase was washed with brine (3 mL) and filtered through a phase separation cartridge. The filtrate was dried by blowing N ₂ to give a crude product, which was purified by reverse phase column chromatography eluting with 5-95% CH ₃ CN / water to give a crude white solid. It was. This solid was purified by trituration with heptane / acetone = 9/1 to give the title compound (78 mg, 65%) as a white solid.
¹ H NMR (400 MHz; d ⁶ -DMSO): δ 3.36 (s, 3H), 7.20 (m, 3H), 7.25 (m, 1H), 7.44 (m, 2H), 7.95 (d, 1H), 8.07 (d, 1H), 8.16 (d, 1H).
LCMS Rt = 2.71 min, MS m / z 471 [MH] ⁺ , 469 [MH] ^- .

Example 101
4-[(6-tert-Butoxy-5-chloropyridin-3-yl) oxy] -5-chloro-2-fluoro-N- (methylsulfonyl) benzamide

To a solution of tert-butyl 3,3-difluorocyclobutanecarboxylate (Preparation Example 227, 126 mg, 0.66 mmol) in toluene (2 mL) was added sodium 1,1,1,3,3,3-hexamethyldisilazane-2- A solution of id (1M in THF, 1.6 mL, 1.6 mmol) was added at 0 ° C. The resulting solution was stirred at the same temperature for 10 minutes and then 5-chloro-4-[(5-chloro-6-fluoropyridin-3-yl) oxy] -2-fluoro-N- (methylsulfonyl) benzamide ( Example 19, 200 mg, 0.50 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 36 hours. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc. The organic phase was washed with 1N aqueous citric acid followed by brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel column chromatography eluting with 0-100% EtOAc / heptane to give a yellow foam. The foam was triturated with heptane to give the title compound (101 mg, 44%) as a white solid.
¹ H NMR (400 MHz; d ⁶ -DMSO): δ 1.58 (s, 9H), 3.35 (br s, 3H), 7.11 (d, 1H), 7.94 (m, 2H), 8.05 (d, 1H).
LCMS Rt = 2.89 min, MS m / z 451 [MH] ⁺ , 449 [MH] ^- .

There is no Example 102.
Example 103
4- (5-Chloro-6- (1,1,1,3,3,3-hexafluoropropan-2-yloxy) pyridin-3-ylamino) -N- (methylsulfonyl) benzamide

4- (5-Chloro-6- (1,1,1,3,3,3-hexafluoropropan-2-yloxy) pyridin-3-ylamino) benzoic acid (Preparation Example 259, 116 mg, 0.27 mmol) To a dichloromethane (5 mL) solution was added 4-dimethylaminopyridine (50 mg, 0.41 mmol) and N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (77 mg, 0.41 mmol). The solution was stirred at room temperature for 25 minutes and methanesulfonamide (39 mg, 0.41 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The solution was concentrated in vacuo and the material was purified by reverse phase chromatography eluting with acetonitrile: water (5:95 to 95: 5, 30 min gradient followed by 5 min isocratic elution) The title compound was obtained as a white solid (98 mg, 74%).
LCMS rt = 3.38min, m / z 492 [MH] ^+
1 H NMR (400MHz, CDCl ₃ ): δ 3.30 (s, 3H), 7.00-7.15 (m, 3H), 7.85 (m, 2H), 7.90 (s, 1H), 8.05 (s, 1H), 8.90 ( s, 1H).

Example 104
5-Chloro-4- (6-cyclopropyl-5- (1,1-difluoroethoxy) pyridin-3-yloxy) -2-fluoro-N- (methylsulfonyl) benzamide hydrochloride

5-Chloro-4- (6-cyclopropyl-5- (1,1-difluoroethoxy) pyridin-3-yloxy) -2-fluorobenzoic acid (Preparation Example 271, 220 mg, 0.57 mmol) in dichloromethane (10 mL) To the solution was added methanesulfonamide (64 mg, 0.68 mmol), HATU (259 mg, 0.68 mmol) and DIPEA (0.35 mL, 1.99 mmol). The reaction was kept stirring at room temperature for 2 hours. The reaction was washed with 2M aqueous HCl (50 mL) and extracted with DCM (3 × 50 mL). The combined organics were dried over MgSO ₄ , filtered and the solvent removed to give an off-white solid. This solid was triturated with a minimum amount of methanol, filtered and dried in air to give the title compound as a white solid such as the HCl salt (131 mg, 50%).
LCMS Rt = 2.64 min, MS m / z 465 [MH] ^+
1 HNMR (400 MHz, CDCl ₃ ): δ 0.91-1.02 (m, 4H), 2.02 (t, 3H), 2.30-2.39 (m, 1H), 3.35 (s, 3H), 7.12 (d, 1H), 7.41 (s, 1H), 7.93 (d, 1H), 8.26 (s, 1H).

Example 105
5-Chloro-2-fluoro-N- (methylsulfonyl) -4- (6- (2,2,3,3-tetrafluoropropoxy) -5- (trifluoromethyl) pyridin-3-yloxy) benzamide

Methanesulfonamide (89.54 mg, 0.94 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.15 mL, 1.03 mmol) were added to 5-chloro-4- (6- (2,2,3,3-tetrafluoropropoxy) -5- (trifluoromethyl) pyridin-3-yloxy) -2-fluorobenzoic acid 4-methylphenyl (Preparation Example 263, 475 mg, 0.86 mmol) in acetonitrile (5 mL) was added to the solution and the reaction mixture was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and water, the organic layer was partitioned, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The crude product was purified by reverse phase chromatography (both acetonitrile / water with 0.1% formic acid) to give the title compound as a white solid (303 mg, 55%).
LCMS Rt = 2.97 min, MS m / z 543 [MH] ^+
1 HNMR (400 MHz, CDCl ₃ ): δ 3.43 (s, 3H), 4.85 (t, 2H), 6.16-5.87 (m, 1H), 6.61 (d, 1H), 7.73 (d, 1H), 8.19 ( s, 1H), 8.27 (d, 1H), 8.65 (br s, 1H).
The following compounds were prepared using methanesulfonamide by methods analogous to Methods M, B and E as described above for Examples 22, 2 and 7. Unless otherwise indicated, the details of the preparation are as described for the referenced method.

  Examples 114-152

To the amine (0.105 mmol) of formula R ⁷ R ⁸ NH (wherein R ⁷ and R ⁸ are as defined above for compounds of formula (I) unless otherwise indicated) [(5-Chloro-6-fluoropyridin-3-yl) oxy] -2,5-difluoro-N- (methylsulfonyl) benzamide (Preparation 30, 28.6 mg, 0.075 mmol) in DMSO (0.6 mL ) Solution, cesium fluoride (23 mg, 0.15 mmol) and DIPEA (39 μL, 0.225 mmol) were added. The reaction mixture was shaken in a sealed bottle at 80 ° C. for 16 hours. The reaction mixture was HPLC (column: DIKMA Diamonsil (2) C18 (200 × 20 mm × 5 um) or Boston Symmetrix ODS-H (150 × 30 mm × 5 um), eluent: acetonitrile: water (containing 0.225% formic acid) , Gradient: 10:90 to 85:15) to give the title compound.

  Examples 153-201

Here, Het ¹ is as defined above for the compound of formula (I) and Lg is as defined above (eg halo).
To a solution of 2,5-difluoro-4-hydroxy-N- (methylsulfonyl) benzamide (Preparation Example 34, 0.10 mmol) in DMSO or NMP (1 mL), cesium carbonate or potassium carbonate (0.20 mmol) and Het ¹ Lg A solution of (Het ¹ Lg, 0.13 mmol) in DMSO or NMP (1 mL) was added and the mixture was heated in a sealed bottle at 100-150 ° C. for 5-16 hours. The reaction mixture was purified by HPLC (column: DIKMA Diamonsil (2) C18 (200 x 20 mm x 5 um) or Boston Symmetrix ODS-H (150 x 30 mm x 5 um) or Agella Venusil ASB C18 (150 x 21.2 mm x 5 um) or Kromasil Purify with Eternity-5-C18 (150 × 30 mm × 5 um), eluent: acetonitrile: water (containing 0.225% formic acid) or acetonitrile: aqueous NH ₄ OH (pH 10), gradient: 0-76%) The title compound was obtained. Unless otherwise stated, the MS (m / z) data given is for [MH] ⁺ ions.

The following compounds of formula (I) were prepared using appropriate reagents and conditions according to the procedures described in the above schemes, examples and corresponding preparations, or by methods analogous to either one of them: . Unless otherwise stated, the MS (m / z) data given is for [MH] ⁺ ions.

Preparation Example 1
4-[(5-Chloro-6-isobutoxypyridin-3-yl) oxy] -3-cyanobenzoic acid

5-Chloro-6-isobutoxypyridin-3-ol (Preparation Example 16, 0.124 g, 0.62 mmol) and potassium carbonate (0.28 g, 2.03 mmol) were suspended in DMSO (3.0 mL). . Then 3-cyano-4-fluorobenzoic acid (0.0835 g, 0.51 mmol) was added in several portions. The reaction was then stirred in nitrogen at 90 ° C. for 16 hours, diluted with EtOAc (15 mL) and washed twice with aqueous HCl (2.0 M, 10 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography (ISCO®, gradient: 5-95% acetonitrile / water, 13 g C18 column) to give the title compound as an orange oil (0.21 g, 120%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 0.98-0.99 (d, 6H), 2.04-2.09 (m, 1H), 4.12 (d, 2H), 7.03 (d, 1H), 8.09-8.13 ( m, 2H), 8.17 (d, 1H), 8.32 (d, 1H).
LCMS Rt = 1.61 min, MS m / z 347 [MH] ⁺ .

Preparation Example 2
(3,3-Difluorocyclobutyl) methanol

3,3-Difluorocyclobutanecarboxylic acid (5.0 g, 36.7 mmol) was dissolved in THF (50.0 mL), and the reaction was cooled to 0 ° C. in an ice bath in nitrogen. Then thiodimethane-borane (1: 1) (5.23 mL, 61.4 mmol) was added dropwise and the mixture was stirred at 0 ° C. for 4 hours. After addition of aqueous HCl (1.0 M, 75 mL) and EtOAc (100 mL), the organic layer was collected and further washed with water (30 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (3.25 g, 73%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 2.15-2.40 (m, 3H), 2.40-2.60 (m, 2H), 3.40 (m, 2H), 4.75 (m, 1H).

Preparation Example 3
3-Chloro-2-[(3,3-difluorocyclobutyl) methoxy] pyridine

Sodium hydride (60% mineral oil dispersion, 1.017 g, 70.6 mmol) was suspended in THF (30.0 mL) and the reaction was cooled to 0 ° C. in an ice bath in nitrogen. A solution of (3,3-difluorocyclobutyl) methanol (Preparation Example 2, 2.95 g, 24.2 mmol) in THF (30 mL) was added dropwise to the mixture while maintaining the temperature at 0 ° C. After stirring for 30 minutes, 2,3-dichloropyridine (3.25 g, 22.0 mmol) was added and the suspension was heated to reflux for 16 hours. Aqueous HCl (1.0 M, 20 mL) was added and the reaction was extracted with EtOAc (2 × 100 mL). The combined organics were then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage®, gradient: 0-50% EtOAc / heptane) to give the title compound (4.82 g, 85%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 2.40-2.50 (m, 2H), 2.60-2.80 (m, 3H), 4.40 (m, 2H), 7.00 (m, 1H), 7.90 (m, 1H), 8.10 (m, 1H).
LCMS Rt = 3.11 min, MS m / z 234 [MH] ⁺ .

Preparation Example 4
3-Chloro-2-[(3,3-difluorocyclobutyl) methoxy] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine

3-Chloro-2-[(3,3-difluorocyclobutyl) methoxy] pyridine (Preparation Example 3, 4.82 g, 20.6 mmol) was dissolved in 1,4-dioxane (50 mL) and 4,4,4 4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (10.48 g, 41.2 mmol) was added. The reaction mixture was degassed and di-μ-methanolatodiiridium (Ir-Ir) -cycloocta-1,5-diene (1: 2) (0.41 g, 0.62 mmol) and 4,4 ′. -Di-tert-butyl-2,2'-bipyridine (0.33 g, 1.23 mmol) was also added. The reaction mixture was then stirred at room temperature for 60 hours under nitrogen. Foaming was observed when methanol (20 mL) was added. When bubbling ceased, the mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Biotage®, gradient: 0-40% EtOAc / heptane) to give the title compound (6.4 g, 86 %):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 1.30 (s, 12H), 2.50 (m, 2H), 2.60-2.80 (m, 3H), 4.40 (m, 2H), 7.90 (s, 1H) , 8.30 (s, 1H).
LCMS Rt = 5.24 min.

Preparation Example 5
5-Chloro-6-[(3,3-difluorocyclobutyl) methoxy] pyridin-3-ol

3-chloro-2-[(3,3-difluorocyclobutyl) methoxy] -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (Preparation Example 4) , 4.5 g, 12.5 mmol) was suspended in methanol (30 mL). Hydrogen peroxide (1.6 mL, 21.3 mmol) was added and the mixture was stirred in nitrogen at room temperature for 16 hours. Aqueous thiosulfite (10%, 10 mL) was added and the mixture was extracted with EtOAc (2 × 200 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage®, gradient: 0-50% EtOAc / heptane) to give the title compound (2.53 g, 81%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 2.50 (m, 2H), 2.60-2.80 (m, 3H), 4.25 (m, 2H), 7.35 (s, 1H), 7.60 (s, 1H) , 9.75 (s, 1H).
LCMS Rt = 2.50 min, MS m / z 248 [MH] ^- .

Preparation Example 6
Tert-Butyl 2,4,5-trifluorobenzoate

2,4,5-trifluorobenzoic acid (10.0 g, 56.8 mmol) was dissolved in tert-butanol (280 mL). Di-tert-butyl dicarbonate (24.8 g, 114 mmol) was added, followed by DMAP (0.694 g, 5.68 mmol) in several portions and the mixture was stirred at 30 ° C. under nitrogen for 16 hours. EtOAc (400 mL) was added and the mixture was washed with aqueous HCl (1.0 M, 2 × 50 mL), then saturated aqueous sodium bicarbonate (2 × 50 mL), and finally brine (2 × 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless oil (12.31 g, 93%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.58 (s, 9H), 6.93-6.99 (m, 1H), 6.68-6.74 (m, 1H).

Preparation Example 7
4-({5-Chloro-6-[(3,3-difluorocyclobutyl) methoxy] pyridin-3-yl} oxy) -2,5-difluorobenzoate tert-butyl

Tert-Butyl 2,4,5-trifluorobenzoate (Preparation Example 6, 0.200 g, 0.86 mmol), 5-chloro-6-[(3,3-difluorocyclobutyl) methoxy] pyridin-3-ol (Preparation Example 5, 0.258 g, 1.03 mmol) and potassium carbonate (0.178 g, 1.29 mmol) were suspended in DMSO (5.0 mL). The mixture was stirred at room temperature for 16 hours under nitrogen. EtOAc (50 mL) was added and the mixture was washed with water (3 × 150 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.400 g, 101%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 1.50 (s, 9H), 2.50 (m, 2H), 2.60-2.80 (m, 3H), 4.40 (m, 2H), 7.10 (m, 1H) , 7.75 (m, 1H), 8.00 (s, 1H), 8.10 (s, 1H).
LCMS Rt = 4.75 min, MS m / z 462 [MH] ⁺ .

Preparation Example 8
4-({5-Chloro-6-[(3,3-difluorocyclobutyl) methoxy] pyridin-3-yl} oxy) -2,5-difluorobenzoic acid

4-({5-Chloro-6-[(3,3-difluorocyclobutyl) methoxy] pyridin-3-yl} oxy) -2,5-difluorobenzoate (Preparation Example 7, 0.400 g, 0.87 mmol) was dissolved in THF (5.0 mL) and methanol (5.0 mL). Aqueous sodium hydroxide (3.0 M, 5.0 mL) was then added and the mixture was stirred in nitrogen at room temperature for 3 hours. Aqueous HCl (1.0 M, 75.0 mL) was added and the mixture was extracted with EtOAc (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (Trilution method) to give the title compound (0.31 g, 88%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 2.50 (m, 2H), 2.60-2.80 (m, 3H), 4.40 (m, 2H), 7.10 (m, 1H), 7.80 (m, 1H) , 8.00 (s, 1H), 8.10 (s, 1H).
LCMS Rt = 3.53 min, MS m / z 404 [MH] ^- .

Preparation Example 9
4-[(5-Chloro-6-isopropoxypyridin-3-yl) oxy] -2,5-difluorobenzoic acid 4-methylphenyl

4-Methylphenyl 2,4,5-trifluorobenzoate (Preparation Example 12, 1.00 g, 3.54 mmol) and potassium carbonate (1.66 g, 12.04 mmol) were suspended in DMSO (24 mL). 5-Chloro-6-isopropoxypyridin-3-ol (Preparation Example 15, 651 mg, 3.47 mmol) was added in several portions over 5 minutes. The mixture was stirred at room temperature for 60 minutes and then partitioned between water (100 mL) and EtOAc (2 × 75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give a green oil (2.5 g) that crystallized on standing. This solid was triturated with heptane to give the title compound as a colorless solid (1.01 g, 65%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.42-1.43 (d, 6H), 2.38 (s, 3H), 5.30-5.40 (m, 1H), 6.67-6.71 (m, 1H), 7.08-7.11 ( m, 2H), 7.21-7.25 (m, 2H), 7.48-7.49 (d, 1H), 7.91-7.95 (m, 2H).
LCMS Rt = 1.81 min, MS m / z 434 [MH] ⁺ .

Preparation Example 10
2-piperidin-1-ylpyrimidin-5-ol

A solution of 5-bromo-2-piperidin-1-ylpyrimidine (1.00 g, 4.15 mmol) in freshly distilled THF (5.2 mL) was replaced with argon and cooled to -78 ° C. To the cooled reaction mixture, n-butyllithium in hexane (2.5 M, 1.99 mL, 4.98 mmol) was added dropwise. The reaction mixture was stirred at −78 ° C. for 10 minutes and then added dropwise to a solution of trimethyl borate (0.559 mL, 4.98 mmol) in THF (5.2 mL) over 10 minutes, which was replaced with argon, and 0 ° C. Until cooled. The resulting reaction mixture was stirred at 0 ° C. for an additional 20 minutes before acetic acid (0.356 mL, 6.22 mmol) was added. After further stirring for 5 minutes, 30% aqueous hydrogen peroxide solution (0.517 mL, 4.57 mmol) was added dropwise, and stirring was continued at 0 ° C. for 5 minutes. Saturated aqueous sodium bisulfite solution (50 mL) was added and the mixture was extracted with EtOAc. The organic extract was washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered through Celite ™ and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 25% EtOAc / hexanes to give the title compound (728 mg, 98%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.40-1.70 (br, 6H), 3.55-3.75 (br, 4H), 8.05 (d, 2H).
MS m / z 180 [MH] ⁺ , 178 [MH] ^-
Theoretical value of CHN-C: 60.32%, H: 7.31%, N: 23.45%
Found for CHN-C: 60.32%, H: 7.43%, N: 23.10%.

Preparation Example 11
Methyl 5-chloro-2,4-difluorobenzoate

  A solution of 5-chloro-2,4-difluorobenzoic acid (2.8 g, 15 mmol) dissolved in HCl in methanol (4 M, 10 mL) was stirred at 60 ° C. for 4 hours. The reaction was cooled and the solvent was evaporated to give the title compound, which was used in the next step without further purification.

Preparation Example 12
2,4,5-trifluorobenzoic acid 4-methylphenyl

  Thionyl chloride (50 mL, 680 mmol) was added to 2,4,5-trifluorobenzoic acid (10 g, 57 mmol) and the mixture was stirred at 55 ° C. for 18 hours. After cooling, excess thionyl chloride was removed in vacuo. The resulting crude oil was azeotroped with DCM (30 mL) and toluene (20 mL) and the residue was redissolved in DCM (50 mL) and then cooled to 0 ° C. with an ice bath. A mixture of 4-methylphenol (6.4 g, 59 mmol) and triethylamine (10 mL, 71 mmol) in DCM (20 mL) was added over 30 minutes. The reaction was left to warm to room temperature over 1 hour. The crude reaction mixture was partitioned between EtOAc (200 mL) and saturated sodium bicarbonate (70 mL). The aqueous layer was further extracted with EtOAc (100 mL). The combined organic extracts were combined and washed with saturated sodium bicarbonate solution (70 mL) and water (100 mL). The organic layer was dried over magnesium sulfate and concentrated to give a crude solid that was purified by silica gel chromatography eluting with 5% EtOAc / heptane to give the title compound (10.08 g, 66%) as white. As a solid.

The title compound can also be prepared according to the following method.
4-Methylphenol (80.0 g, 739.8 mmol) was added to 2,4,5-trifluorobenzoic acid (136.8 g, 776.8 mmol) and 1,1-carbonyldiimidazole (83-85% wt, 163 .6 g, 849.7 mmol) in EtOAc (1.20 L) was added at 40 ° C. The reaction mixture was stirred at 40 ° C. for 2 hours, then cooled to 20 ° C. and washed with water (480 mL), 0.5 M aqueous sodium hydroxide (2 × 400 mL) and water (400 mL). The organics were concentrated in vacuo and azeotroped with heptane to give a yellow oil. Heptane (640 mL) was added and the reaction was stirred at room temperature for 16 hours. A seed crystal was used to facilitate the formation of a suspension. The resulting suspension was cooled to 10 ° C. and filtered. The residue was washed with cold heptane (80 mL) and dried to give the title compound as an off-white solid (147.5 g, 75%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.40 (s, 3H), 7.10 (m, 3H), 7.24 (m, 2H), 7.95 (m, 1H).
LCMS Rt = 3.53 min.

Preparation Example 13
3-chloro-2-isopropoxypyridine

2-Propanol (128 mL, 1.07 mol) was added dropwise to a suspension of sodium hydride (64.10 g, 1.07 mol) in THF (1.65 L) at 5 ° C. over 50 minutes. The reaction mixture was then warmed to room temperature and stirred for 1 hour. 2,3-dichloropyridine (154.6 g, 1.11 mol) was added and the reaction mixture was gently heated to reflux and kept stirring for 18 hours. The reaction mixture was cooled to 5-10 ° C. and carefully quenched with a brine: water mixture (50:50, 100 mL) and then water (300 mL). The aqueous layer was extracted with EtOAc (3 × 600 mL). The combined organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound as a dark red oil (164.1 g, 89%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.40 (d, 6H), 5.36 (m, 1H), 6.80 (m, 1H), 7.6 (m, 1H), 8.05 (m, 1H).
LCMS Rt = 3.09 min.

Preparation Example 14
3-Chloro-2-isopropoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine

3-chloro-2-isopropoxypyridine (Preparation Example 13, 154.1 g, 897.9 mmol), bis (pinacolato) diboron (273.6 g, 1077.4 mmol), 4,4-di-tert-butyl-2, 2-dipyridyl (2.459 g, 8.979 mmol) was added to heptane (400 mL) followed by di-μ-methanolatodiiridium (Ir-Ir) -cycloocta-1,5-diene (1: 2) (0. 193 g, 0.2914 mmol). The reaction was stirred at room temperature for 18 hours, quenched with MeOH and concentrated to dryness to give the title compound as a reddish brown oil (479 g). The product was used in the next step without further purification.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.32 (s, 12H), 1.38 (d, 6H), 5.41 (m, 1H), 6.75 (m, 1H), 7.94 (d, 1H), 8.37 (d , 1H).
LCMS Rt = 5.10 min, m / z 256 [MH] ⁺ .

Preparation Example 15
5-chloro-6-isopropoxypyridin-3-ol

Peracetic acid (191 mL, 1077 mmol) was added to 3-chloro-2-isopropoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (Preparation Example 14, 479 g of crude material, 897.9 mmol) in case of 100% yield in previous Preparation Example 14) was added at 5-10 ° C. The reaction was slowly warmed to room temperature over 4 hours, concentrated to 10% volume and extracted with EtOAc. The resulting crude material was purified by silica gel chromatography eluting with 50% EtOAc / heptane to give the title compound as a white solid (110 g, 65%, two steps combined).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.35 (d, 6H), 5.19 (m, 1H), 7.26 (d, 1H), 7.68 (d, 1H).
LCMS Rt = 2.10 min, m / z 186 [MH] ⁺ .

Preparation Example 16
5-chloro-6-isobutoxypyridin-3-ol

To a suspension of 5-chloro-6-isobutoxypyridin-3-ylboronic acid (3.02 g, 13.1 mmol) in acetic acid / water (1: 1, 20 mL) cooled to 0 ° C., peracetic acid (3.9 mL) 20.0 mmol) was added slowly and the reaction mixture was maintained at 0 ° C. for 1.5 hours and then at room temperature for 1 hour. Additional peracetic acid (3.9 mL, 20.0 mmol) was added and the reaction was stirred at room temperature for 40 minutes before dissolving the suspension. The reaction mixture was quenched with sodium thiosulfate solution (15 mL) and stirred for 5 minutes. The mixture was extracted with EtOAc (2 × 30 mL) and the combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give a yellow oil (3.66 g). The oil was purified by silica gel chromatography (Biotage ™ 50 g) eluting with 80-100% methanol / DCM to give the title compound as a white solid (1.94 g, 73%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.02 (d, 6H), 2.11 (m, 1H), 4.05 (d, 2H), 6.03 (br, 1H), 7.31 (d, 1H), 7.65 (d , 1H).
LCMS Rt = 2.51 min, MS m / z 200 [MH] ^- .

Preparation Example 17
Lithium salt of 4- (5-chloro-6-methoxypyridin-3-yloxy) -2,5-difluorobenzoic acid

Aqueous lithium hydroxide (1M, 0.88 mL, 0.88 mmol) was added to tert-butyl 4- (5-chloro-6-methoxypyridin-3-yloxy) -2,5-difluorobenzoate (Preparation Example 18, 65 mg). , 0.176 mmol) in THF (2 mL) and stirred overnight at room temperature in a nitrogen atmosphere. The reaction was then concentrated in vacuo to give the title compound as a lithium salt (59 mg, 107%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.95 (s, 3H), 6.57 (m, 1H), 7.38 (d, 1H), 7.83 (m, 1H), 8.04 (d, 1H).
LCMS Rt = 3.12 min, MS m / z 316 [MH] ⁺ .

Preparation Example 18
Tert-Butyl 4- (5-chloro-6-methoxypyridin-3-yloxy) -2,5-difluorobenzoate

5-chloro-6-methoxypyridin-3-ol (Preparation Example 77, 100 mg, 0.627 mmol), tert-butyl 2,4,5-trifluorobenzoate (Preparation Example 6, 147 mg, 0.633 mmol) and carbonic acid A mixture of potassium (260 mg, 1.88 mmol) in DMSO (5 mL) was stirred overnight at 25 ° C. in a nitrogen atmosphere. The reaction was diluted with water (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organics were washed with aqueous sodium hydroxide (1.0 M, 30 mL), brine (2 × 40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 5% EtOAc / heptane to give the title compound as a white solid (65 mg, 28%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.59 (s, 9H), 3.95 (s, 3H), 6.57 (m, 1H), 7.29 (s, 1H), 7.70 (m, 1H), 8.00 (s , 1H).
LCMS Rt = 3.98 min, MS m / z 372 [MH] ⁺ .

Preparation Example 19
5-chloro-6-cyclobutoxypyridin-3-ol

A solution of peracetic acid in acetic acid (35%, 4.2 mL, 21.3 mmol) was added to 3-chloro-2-cyclobutoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) pyridine (Preparative Example 20, 4.4 g, 14.2 mmol) was added to a solution of glacial acetic acid (26 mL) and water (13 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hour. Aqueous sodium thiosulfate (0.5M, 80 mL) was added and the mixture was stirred at room temperature for 30 minutes. The aqueous layer was extracted with EtOAc (3 × 40 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 10% EtOAc / heptane to give the title compound as a clear oil (2.05 g, 72%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.67 (m, 1H), 1.83 (m, 1H), 2.17 (m, 2H), 2.45 (m, 2H), 5.13 (m, 1H), 5.60 (s , 1H), 7.27 (m, 1H), 7.65 (m, 1H).
LCMS Rt = 2.44 min, MS m / z 202 [MH] ⁺ .

Preparation Example 20
3-Chloro-2-cyclobutoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine

3-Chloro-2-cyclobutoxypyridine (Preparation Example 21, 3.7 g, 20.1 mmol) and bis (pinacolato) diboron (5.6 g, 22.1 mmol) were suspended in heptane (35 mL) and degassed with nitrogen did. 4,4′-Di-tert-butyl-2,2′-dipyridyl (54 mg, 0.20 mmol) and (1,5-cyclooctadiene) (methoxy) iridium (I) dimer (67 mg, 0.10 mmol) ) And the resulting suspension was degassed with nitrogen and stirred at room temperature for 16 hours in nitrogen. After dropwise addition of methanol (10 mL), the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 20% EtOAc / heptane to give the title compound as a clear oil (4. 4g, 71%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.32 (s, 12H), 1.68 (m, 1H), 1.84 (m, 1H), 2.19 (m, 2H), 2.48 (m, 2H), 5.29 (m , 1H), 7.94 (m, 1H), 8.35 (m, 1H).
LCMS Rt = 4.42 min, MS m / z 310 [MH] ⁺ .

Preparation Example 21
3-chloro-2-cyclobutoxypyridine

Sodium hydride dispersoid (60%, 1.22 g, 30.5 mmol) was suspended in anhydrous THF (40 mL) under a nitrogen atmosphere. A solution of cyclobutanol (2.0 g, 27.7 mmol) in THF (10 mL) was added dropwise at room temperature, and the reaction system was stirred at room temperature for 1 hour. 2,3-Dichloropyridine (5.0 g, 33.8 mmol) was added and the reaction mixture was stirred at 60 ° C. in nitrogen for 16 hours. Water (50 mL) was added and the reaction mixture was concentrated in vacuo. The aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 3% EtOAc / heptane to give the title compound as a clear oil (3.7 g, 72%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.70 (m, 1H), 1.87 (m, 1H), 2.22 (m, 2H), 2.50 (m, 2H), 5.25 (m, 1H), 6.83 (m , 1H), 7.61 (m, 1H), 8.05 (m, 1H).
LCMS Rt = 2.99 min, no molecular ions were observed.

Preparation Example 22
4-{[5-Chloro-6- (tetrahydro-2H-pyran-4-yloxy) pyridin-3-yl] oxy} -2,5-difluorobenzoic acid

Trifluoroacetic acid (5 mL) was added to tert-butyl 4-{[5-chloro-6- (tetrahydro-2H-pyran-4-yloxy) pyridin-3-yl] oxy} -2,5-difluorobenzoate (preparation). Example 23, 0.28 g, 0.64 mmol) in DCM (10 mL) was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil that was purified by silica gel chromatography eluting with EtOAc to give an off-white solid. . This solid was triturated with 4: 1 = heptane: EtOAc to give the title compound as a white solid (0.24 g):
¹ H NMR (400 MHz, CD ₃ OD): δ 1.72-1.85 (m, 2H), 2.03-2.12 (m, 2H), 3.57-3.67 (m, 2H), 3.91-3.99 (m, 2H), 5.32 (m, 1H), 6.80-6.86 (m, 1H), 7.74-7.81 (m, 1H), 7.96 (s, 1H).
LCMS Rt = 2.70 min, MS m / z 385 [MH] ⁺ .

Preparation Example 23
4-{[5-Chloro-6- (tetrahydro-2H-pyran-4-yloxy) pyridin-3-yl] oxy} -2,5-difluorobenzoate tert-butyl

Potassium carbonate (0.14 g, 1.63 mmol) was added to DMSO of 5-chloro-6- (tetrahydro-2H-pyran-4-yloxy) pyridin-3-ol (Preparation Example 24, 0.23 g, 0.65 mmol). (10 mL) was added to the solution. After 1 minute, 2,4,5-trifluoro-tert-butyl ester (Preparation Example 6, 0.24 g, 0.69 mmol) was added in one portion and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with aqueous sodium hydroxide (1M, 100 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow oil that was used in the next step without further purification (0.28 g, 98% ):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.61 (s, 9H), 1.80-1.91 (m, 2H), 2.03-2.11 (m, 2H), 3.57-3.67 (m, 2H), 3.95-4.04 ( m, 2H), 5.22-5.31 (m, 1H), 6.56-6.64 (m, 1H), 7.23 (s, 1H), 7.69-7.74 (m, 1H), 7.86 (s, 1H).
LCMS Rt = 4.76 min, MS m / z 442 [MH] ⁺ .

Preparation Example 24
5-Chloro-6- (tetrahydro-2H-pyran-4-yloxy) pyridin-3-ol

3-Chloro-2- (tetrahydro-2H-pyran-4-yloxy) pyridine (Preparation 25, 1.40 g, 6.55 mmol) and bis (pinacolato) diboron (6.65 g, 13.11 mmol) in heptane (30 mL) ) And degassed 5 times with nitrogen. Di-tert-butyldipyridyl (0.017 mg, 0.066 mmol) was added followed by (1,5-cyclooctadiene) (methoxy) iridium (I) dimer (0.022 mg, 0.033 mmol). The mixture was again degassed with nitrogen five times and stirred at room temperature for 18 hours. The reaction is quenched by slow addition of methanol (50 mL) and concentrated in vacuo to give a red / orange oil which is purified by silica gel chromatography eluting with 66% EtOAc / heptane, An impure product was obtained. The resulting crude product was dissolved and a 1: 1 mixture of acetic acid: water (30 mL) was added and cooled to 5 ° C. (ice bath). Peracetic acid was added slowly over 2 minutes. The reaction system was stirred at 5 ° C. for 30 minutes, and 1M aqueous sodium thiosulfate solution was added. The reaction was allowed to warm slowly to room temperature over 30 minutes, diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were then dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil that was purified by silica gel chromatography eluting with EtOAc to give an off-white solid. Obtained. This solid was triturated with heptane to give the title compound as a white solid (0.483 g, 43%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.79-1.90 (m, 2H), 2.01-2.12 (m, 2H), 3.58-3.68 (m, 2H), 3.95-4.08 (m, 2H), 5.18 ( m, 1H), 7.27 (s, 1H), 7.63 (s, 1H).
LCMS Rt = 1.72 min, MS m / z 230 [MH] ⁺ .

Preparation Example 25
3-Chloro-2- (tetrahydro-2H-pyran-4-yloxy) pyridine

Tetrahydro-2H-pyran-4-ol (1.03 g, 10.1 mmol) was added to a suspension of NaH (60% mineral oil) (0.41 g, 10.16 mmol) in anhydrous THF (20 mL) at 5 ° C. (Ice bath) was added slowly over 1 minute. The suspension was then warmed to room temperature. After 30 minutes, 2,3-dichloropyridine (1.00 g, 6.76 mmol) was added and the reaction was heated at 70 ° C. for 18 hours. The reaction system was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with EtOAc (3 × 50 mL). The combined organics were then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow oil that was used in the next step without further purification (1.40 g, 98% ):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.60-2.10 (m, 4H), 3.58-3.67 (m, 2H), 3.95-4.04 (m, 2H), 5.32 (m, 1H), 6.81 (m, 1H), 7.62 (d, 1H), 8.00 (d, 1H).
LCMS Rt = 2.53 min, no molecular ion was observed.

Preparation Example 26
4-Methylphenyl 5-chloro-2,4-difluorobenzoate

5-Chloro-2,4-difluorobenzoic acid (1.17 g, 6.08 mmol) was dissolved in thionyl chloride (5.0 mL) and heated at 60 ° C. for 5 hours in a nitrogen atmosphere. The reaction mixture was concentrated in vacuo and azeotroped with DCM (2 × 10 mL) and toluene (10 mL). The crude product was then dissolved in DCM (15 mL) and cooled to 0 ° C. A solution of 4-methylphenol (0.665 g, 6.15 mmol) and triethylamine (1.05 mL, 7.53 mmol) in DCM (10 mL) was added dropwise and the reaction mixture was stirred at room temperature for 18 hours in a nitrogen atmosphere. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (10 mL) and then washed with saturated aqueous sodium bicarbonate (2 × 10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a crude solid. This solid was triturated with a minimum amount of heptane to give the title compound as a white solid (1.20 g, 69%):
¹ H NMR (400 MHz; d ₆ -DMSO): δ 7.15-7.20 (d, 2H), 7.25-7.30 (d, 2H), 7.80 (t, 1H), 8.28 (t, 1H).
LCMS Rt = 1.89 min, MS m / z 283 [MH] ⁺ .

Preparation Example 27
2,4,5-trifluoro-N- (methylsulfonyl) benzamide

2,4,5-trifluorobenzoic acid (3.00 g, 17.0 mmol), N-ethyl-N-isopropylpropan-2-amine (8.9 mL, 6.6 g, 51.1 mmol), 2,4, A solution of 6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide in 50% EtOAc / DMF (12.7 mL, 13.6 g, 42.6 mmol). And methanesulfonamide (3.24 g, 34.1 mmol) were suspended in THF (40 mL) and stirred under reflux in a nitrogen atmosphere for 18 hours. The reaction mixture was cooled and concentrated in vacuo and the residue was suspended in water (pH = 4). The mixture was acidified with aqueous potassium hydrogen sulfate (0.5M) to pH = 2. The mixture was extracted with EtOAc (1 × 100 mL). The organic layer was washed with brine (2 × 50 mL), dried over sodium sulfate, filtered and evaporated to give a crude solid. This crude solid was triturated with hexanes to give the title compound as an off-white crystalline solid (3.08 g, 72%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.45 (s, 3H), 7.10-7.13 (m, 1H), 7.97-8.02 (m, 1H), 8.74 (br, 1H).
¹⁹ FNMR (400 MHz, CDCl ₃ ): δ-112.4, -121.9, -138.5.

Preparation Example 28
5-Chloro-2,4-difluoro-N- (methylsulfonyl) benzamide

5-chloro-2,4-difluorobenzoic acid (0.291 g, 1.511 mmol), N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.438 g, 2.285 mmol) and 4- Dimethylaminopyridine (0.420 g, 3.438 mmol) was suspended in DCM (5 mL). Methanesulfonamide (0.222 g, 2.334 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (10 mL) and washed with aqueous HCl (2M, 2 × 15 mL). The organic layer was dried over a phase separation cartridge and concentrated in vacuo to give the title compound as a white solid (0.388 g, 95%):
¹ H NMR (400 MHz; d ₆ -DMSO): δ 3.38 (s, 3H), 7.65 (t, 1H), 7.95 (t, 1H)
LCMS Rt = 1.43 min, MS m / z 268 [MH] ^- .

Preparation Example 29
Butane-2-sulfonamide

Butane-2-sulfonyl chloride (0.800 g, 5.10 mmol) was carefully added to a cooled solution of ammonium hydroxide solution (ca. 35%, 5.00 mL) and the reaction mixture was stirred vigorously for 4 h. The solvent was evaporated in vacuo. The resulting residue was triturated with acetone. The filtrate was evaporated in vacuo and the residue was triturated with EtOAc / heptane (1: 1) to give the title compound as a clear oil (0.487 g, 70%):
¹ H NMR (400 MHz; CDCl ₃ solution): δ 0.95 (t, 3H), 1.20 (t, 3H), 1.35 (m, 1H), 1.90 (m, 1H), 2.75 (m, 1H), 6.60 ( br, 2H).

Preparation Example 30
4-[(5-Chloro-6-fluoropyridin-3-yl) oxy] -2,5-difluoro-N- (methylsulfonyl) benzamide

Methanesulfonamide (52.0 mg, 0.547 mmol) was suspended in MeCN (3 mL) in a sealed bottle. 2,3,4,6,7,8,9,10-octahydropyrimido [1,2-a] azepine (0.085 mL, 0.57 mmol) followed by 4-[(5-chloro-6-fluoro Pyridin-3-yl) oxy] -2,5-difluorobenzoate 4-methylphenyl (Preparation 67, 215.0 mg, 0.546 mmol) was added. The mixture was heated at 45 ° C. for 2 hours. The reaction mixture was diluted with EtOAc (15 mL) and then washed with 10% aqueous citric acid (2 × 15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was partitioned between DCM (10 mL) and water (10 mL). The organic layer was further washed with water (2 × 10 mL) and concentrated in vacuo to give the title compound as a white solid (75 mg). EtOAc (15 mL) was added to the combined aqueous layers. The organic layer was then washed with water (3 × 10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a second batch of the title compound as a white solid (75.0 mg, 35% ):
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.44 (s, 3H), 6.79-6.84 (q, 1H), 7.59-7.62 (m, 1H), 7.95-7.96 (m, 1H), 7.96-8.01 ( q, 1H), 8.71-8.75 (br, 1H).
LCMS Rt = 1.29min, MS m / z 381 [MH] ^+
19 F NMR (400 MHz, CDCl ₃ ): -73.88, -112.29, -132.68.

Preparation Example 31
4-[(5-Chloro-6-isobutoxypyridin-3-yl) oxy] benzamide

4-[(5-Chloro-6-isobutoxypyridin-3-yl) oxy] benzonitrile (Preparation 32, 162 mg, 0.535 mmol) and potassium carbonate (150 mg, 1.085 mmol) in DMSO (3 mL). Suspended. Aqueous hydrogen peroxide (0.250 mL, 8.08 mmol) was added dropwise (exothermic reaction) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (2 × 15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a white solid that was triturated with DCM to give the title compound. The filtrate was concentrated in vacuo and the residue was triturated again with DCM to give a second crop of the title compound as a white solid (85.0 mg, 49% combined for the two recoveries):
¹ H NMR (400 MHz; d ₆ -DMSO): δ 0.97 (s, 3H), 0.98 (s, 3H), 2.05 (m, 1H), 4.10 (d, 2H), 7.01 (d, 2H), 7.29 (br, 1H), 7.85-7.88 (m, 3H), 7.91 (br, 1H), 8.01 (d, 1H).
LCMS Rt = 1.64 min, MS m / z 321 [MH] ⁺ .

Preparation Example 32
4-[(5-Chloro-6-isobutoxypyridin-3-yl) oxy] benzonitrile

5-Chloro-6-isobutoxypyridin-3-ol (Preparative Example 16, 145 mg, 0.719 mmol) and potassium carbonate (400 mg, 2.561 mmol) were dissolved in DMSO (3.00 mL). 4-Fluorobenzonitrile (200 mg, 1.651 mmol) was then added and the mixture was heated at 110 ° C. for 18 hours. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0-20% EtOAc / heptane to give the title compound as a clear oil (162 mg, 74%):
¹ H NMR (400 MHz; d ₆ -DMSO): δ 0.97 (s, 3H), 0.98 (s, 3H), 2.05 (m, 1H), 4.10 (d, 2H), 7.13 (d, 2H), 7.82 (d, 2H), 7.97 (d, 1H), 8.05 (d, 1H).
LCMS Rt = 1.64 min, MS m / z 303 [MH] ⁺ .

Preparation Example 33
4-{[5-Chloro-6- (trifluoromethyl) pyridin-3-yl] oxy} benzaldehyde

5-Chloro-6- (trifluoromethyl) pyridin-3-ol (Preparation Example 83, 250 mg, 1.266 mmol), 4-fluorobenzaldehyde (150 mg, 1.209 mmol) and potassium carbonate (260 mg, 1.881 mmol) To a solution of DMSO (5 mL). The mixture was stirred at 85 ° C. for 18 hours and then at 125 ° C. for 72 hours. The mixture was diluted with EtOAc (15 mL) and washed with water (2 × 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified by silica gel chromatography eluting with 0-20% EtOAc / heptane to give the title compound as a yellow oil (26.5 mg, 70%):
¹ H NMR (400 MHz; CDCl ₃ ): δ 7.20-7.24 (m, 2H), 7.47-7.48 (d, 1H), 7.96-8.00 (m, 2H), 8.37-8.38 (d, 1H), 10.01 ( s, 1H).
LCMS Rt = 1.65 min, no molecular ions were observed.

Preparation Example 34
2,5-difluoro-4-hydroxy-N- (methylsulfonyl) benzamide

A solution of hydrochloric acid in dioxane (4M, 30 mL) was added to 4-tert-butoxy-2,5-difluoro-N- (methylsulfonyl) benzamide (Preparation 35, 1.76 g, 5.73 mmol), resulting in The solution was stirred at room temperature. After 3 hours, the reaction mixture was concentrated in vacuo and the residue was repeatedly azeotroped with DCM to give the title compound as a white solid (1.49 g, 100%):
¹ H NMR (400 MHz; CDCl ₃ ): δ 3.25 (s, 3H), 6.60-6.68 (m, 1H), 7.45-7.55 (m, 1H), 9.80-9.95 (br, 1H), 10.50-10.65 ( br, 1H)
LCMS Rt = 0.72 min, MS m / z 250 [MH] ^- , 252 [MH] ⁺ .

Preparation Example 35
4-tert-Butoxy-2,5-difluoro-N- (methylsulfonyl) benzamide

Potassium tert-butoxide (1.46 g, 13.0 mmol) was added to a solution of 2,4,5-trifluoro-N- (methylsulfonyl) benzamide (Preparation Example 27, 1.5 g, 5.924 mmol) in DMSO (10 mL). And stirred at room temperature. After 3 hours, additional potassium tert-butoxide (140 mg, 1.3 mmol) was added and stirred for an additional 18 hours. The reaction mixture was diluted with EtOAc and 10% aqueous citric acid. The pH of the aqueous layer was acidic. The organic layer was washed with additional 10% aqueous citric acid solution and brine then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a creamy solid (1.76 g, 100%):
¹ H NMR (400 MHz; CDCl ₃ ): δ 1.45 (s, 9H), 3.42 (s, 3H), 6.88-6.93 (m, 1H), 7.80-7.87 (m, 1H), 8.70-8.85 (br, 1H).

Preparation Example 36
5-chloro-4-{[5-chloro-6- (1-fluoro-1-methylethyl) pyridin-3-yl] oxy} -2-fluorobenzoic acid 4-methylphenyl

5-chloro-2,4-difluorobenzoic acid 4-methylphenyl (Preparation Example 26, 141 mg, 0.199 mmol) was converted to 5-chloro-6- (1,1-difluoroethyl) pyridin-3-ol (Preparation Example). 90, 120 mg, 0.51 mmol) and potassium carbonate (115 mg, 0.832 mmol) in DMSO (3 mL) were added and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (3 × 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was then purified by silica gel chromatography eluting with 0-15% EtOAc / heptane to give the title compound (20.8 mg, 23%):
¹ H NMR (400 MHz; CDCl ₃ ): δ 1.83-1.88 (d, 6H), 2.38 (s, 3H), 2.33 (s, 3H), 6.78-6.81 (d, 1H), 7.08-7.11 (m, 2H), 7.22-7.24 (m, 2H), 7.43 (m, 1H), 8.25-8.26 (d, 1H), 8.28-8.29 (m, 1H).
LCMS Rt = 1.87 min, MS m / z 452 [MH] ⁺ .

Preparation Example 37
4-[(5-Chloro-6-isobutoxypyridin-3-yl) oxy] -2,5-difluorobenzoic acid

4-[(5-Chloro-6-isobutoxypyridin-3-yl) oxy] -2,5-difluorobenzoate (Preparation 38, 150 mg, 0.389 mmol) and lithium hydroxide (250 mg, 10.44 mmol) ) Was dissolved in water (2.5 mL) and THF (2.5 mL) and stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and washed with water (10 mL) and aqueous HCl (2M, 10 mL), then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid. (140 mg, 100%):
¹ H NMR (400 MHz; d ₆ -DMSO): δ 0.97 (s, 3H), 0.99 (s, 3H), 2.05 (m, 1H), 4.10 (d, 2H), 7.04-7.08 (q, 1H) , 7.76-7.80 (q, 1H), 8.01 (d, 1H), 8.10 (d, 1H).
LCMS Rt = 1.72 min, MS m / z 358 [MH] ⁺ .

Preparation Example 38
4-[(5-Chloro-6-isobutoxypyridin-3-yl) oxy] -2,5-difluorobenzoic acid ethyl ester

Ethyl 2,4,5-trifluorobenzoate (135 mg, 0.661 mmol) and potassium carbonate (156 mg, 1.129 mmol) were dissolved in DMSO (3.0 mL). 5-Chloro-6-isobutoxypyridin-3-ol (Preparation 16, 127.5 mg, 0.632 mmol) was added in several portions and the mixture was stirred at room temperature for 2 hours. The reaction was diluted with EtOAc (10.0 mL) and washed with brine (3 × 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc / heptane to give the title compound as a clear oil that solidified on standing (155 mg, 35%):
¹ H NMR (400 MHz; d ₆ -DMSO): δ 0.97 (s, 3H), 0.99 (s, 3H), 1.28 (t, 3H), 2.05 (m, 1H), 4.10 (d, 2H), 4.29 (q, 2H), 7.10 (q, 1H), 7.82 (q, 1H), 8.02 (d, 1H), 8.10 (d, 1H).
LCMS Rt = 1.77 min, MS m / z 386 [MH] ⁺ .

Preparation Example 39
1-Isopropyl-1H-indazol-5-ol

5-{[tert-butyl (dimethyl) silyl] oxy} -1-isopropyl-1H-indazole (Preparation Example 40, 238 mg, 0.819 mmol), triethylamine trishydrofluoride (132 mg, 0.819 mmol) and methanol together And stirred at room temperature for 18 hours in a nitrogen atmosphere. The reaction mixture was concentrated in vacuo and the residue was redissolved with methanolic ammonia and again concentrated in vacuo. The above procedure was repeated once more and the residue was purified by silica gel chromatography eluting with 0-30% EtOAc / heptane to give the title compound (123 mg, 86%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.60 (d, 6H), 4.82 (m, 1H), 7.11 (m, 1H), 7.14 (m, 1H), 7.34 (m, 1H), 7.90 (br , 1H).
Ms m / z 177 [MH] ⁺ .

Preparation Example 40
5-{[tert-Butyl (dimethyl) silyl] oxy} -1-isopropyl-1H-indazole

Sodium hydride (60% oil dispersion, 211 mg, 5.28 mmol) was added to 5-{[tert-butyl (dimethyl) silyl] oxy} -1H-indazole (Preparation Example 41, 1.09 g, 4.40 mmol). Add to THF (10 mL) solution and stir at room temperature for 15 min. The solution was then heated to reflux at 50 ° C. for 18 hours and then for 8 hours. The reaction mixture was diluted with EtOAc and washed with water, 0.5N aqueous citric acid and brine, then dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 0-10% EtOAc / heptane to give the title compound as a clear oil (261 mg, 20%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.20 (s, 6H), 1.00 (s, 9H), 1.59 (d, 6H), 4.82 (m, 1H), 6.97 (d, 1H), 7.08 (s , 1H), 7.30 (d, 1H) and 7.89 (s, 1H).
MS m / z 291 [MH] ⁺ .

Preparation Example 41
5-{[tert-Butyl (dimethyl) silyl] oxy} -1H-indazole

5-hydroxyindazole (3.00 g, 22.37 mmol), tert-butyldimethylsilyl chloride (4.05 g, 26.8 mmol) and imidazole (2.28 g, 33.5 mmol) were mixed in DCM (50 mL). And stirred at room temperature for 18 hours. The reaction mixture was taken up in 0.5N aqueous citric acid and extracted with DCM (3 × 25 mL). The combined organics were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc / hexanes to give the title compound as an orange solid (5.09 g, 90%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.21 (s, 6H), 1.00 (s, 9H), 7.11 (d, 1H), 7.13 (s, 1H) 7.52 (d, 1H) and 8.06 (s, 1H), NH was not observed.
MS m / z 249 [MH] ⁺ , 247 [MH] ^- .

Preparation Example 42
6-Chloroquinolin-8-ol

6-Chloro-8-methoxyquinoline (Preparation Example 43, 10 g, 51.6 mmol) was added to pyridine hydrochloride (43 g, 375 mmol) and the mixture was heated at 150 ° C. for 1 hour. The reaction mixture was diluted with water (200 mL), basified with saturated aqueous sodium bicarbonate solution to pH = 8, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 5-10% EtOAc / petroleum ether to give the title compound as a pale yellow solid (5.6 g, 70%):
¹ H NMR (300 MHz, CDCl ₃ ): δ 4.76 (br, 1H), 7.16 (m, 1H), 7.33 (m, 1H), 7.46 (m, 1H), 8.06 (m, 1H), 8.76 (m , 1H).

Preparation Example 43
6-Chloro-8-methoxyquinoline

Concentrated sulfuric acid (40 mL) was added 4-chloro-2-anisidine hydrochloride (20 g, 127 mmol), m-nitrobenzenesulfonic acid sodium salt (42.4 g, 190 mmol), boric acid (10 g, 161.8 mmol), sulfuric acid first To a mixture of iron (6.0 g, 21.5 mmol) and glycerin (400 mL) was added at room temperature. The mixture was heated at 140 ° C. for 30 minutes. The reaction mixture was diluted with water (500 mL) and the pH was adjusted to 10 with 10% aqueous sodium hydroxide. DCM (1 L) was added and stirred for 30 minutes, filtered through celite and the layers were separated. The aqueous layer was extracted with DCM (2 × 500 mL) and the combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 20% EtOAc / petroleum ether to give the title compound as a liquid (14.2 g, 58%):
¹ H NMR (300 MHz, CDCl ₃ ): δ 4.09 (s, 3H), 7.01 (m, 1H), 7.38 (m, 1H), 7.46 (m, 1H), 8.03 (m, 1H), 8.90 (m , 1H).

Preparation Example 44
2-Isopropoxypyrimidin-5-ol

An aqueous solution (5 mL) of potassium peroxymonosulfate (1.40 g, 2.27 mmol) was added to 2-isopropoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl). To a solution of pyrimidine (Preparation Example 45, 500 mg, 1.89 mmol) in acetone (5 mL) was added dropwise at 0 ° C. in a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours then filtered and the filtrate was diluted with water (30 mL) and extracted with EtOAc (1 × 20 mL). The organic layer was washed with brine (2 × 20 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The resulting oil was dissolved in DCM and purified by silica gel chromatography eluting with 0-5% MeOH (including 10% aqueous ammonia) / DCM to give a solid. This solid was suspended in diethyl ether and evaporated to give the title compound as a white solid (100 mg, 34%):
¹ H NMR (400 MHz; CDCl ₃ ): δ 1.37 (d, 6H), 1.97 (br, 1H), 5.14-5.31 (m, 1H), 8.20 (s, 2H).
LCMS Rt = 10 min, Ms m / z 153 [MH] ^- .

Preparation Example 45
2-Isopropoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine

5-bromo-2-isopropoxypyrimidine (171.0 g, 787.8 mmol), bis (pinacolato) diboron (290.0 g, 1142.0 mmol), potassium acetate (237.0 g, 2360 mmol) and 1,1 ′ dichloride -Bis (diphenylphosphino) ferrocenepalladium (9.10 g, 12.44 mmol) was mixed in dioxane (1.0 L) under nitrogen at room temperature. The mixture was heated at 95 ° C. for 30 minutes and then at 105 ° C. until the reaction was complete. The solution was diluted with water (1000 mL) and DCM (2 L) and then filtered through celite. The layers were separated and the organic layer was washed with water (1 L), dried over sodium sulfate, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography eluting with 0-5% EtOAc / hexanes to give the title compound as a white solid (162 g, 54%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 1.30-1.32 (m, 10H), 5.22-5.28 (m, 1H), 8.70 (s, 2H).
Molecular ions were not observed.

Preparation Example 46
6-Isopropoxypyridin-3-ol

5-Chloro-6-isopropoxypyridin-3-ol (0.288 g, 1.54 mmol) was dissolved in absolute ethanol (5 mL) and heated to reflux. Then 10% palladium on carbon (0.085 g, 0.799 mmol) and ammonium formate (1.35 g, 0.0214 mol) were added and the mixture was stirred at reflux under nitrogen for 1 hour. The reaction mixture was filtered through a pad of arbocel® under a stream of nitrogen and washed with MeOH (15 mL). The filtrate was concentrated in vacuo. The resulting crude product was then diluted with EtOAc (20 mL) and washed with water (30 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid (0.23 g, 97%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 1.20-1.22 (d, 6H), 5.00-5.09 (m, 1H), 6.54-6.56 (d, 1H), 7.10-7.13 (m, 1H), 7.63-7.64 (d, 1H), 9.18 (s, 1H)
LCMS Rt = 0.72 min, MS m / z 154 [MH] ⁺ .

Preparation Example 47
3-Chloro-2-iodopyridine

2-Bromo-3-chloropyridine (6.25 g, 0.033 mol) and sodium iodide (14.5 g, 0.10 mol) were dissolved in propionitrile (26 mL). Chloro (trimethyl) silane (4.1 mL, 32 mmol) was then added dropwise to the mixture. After bubbling ceased, the reaction mixture was refluxed in nitrogen for 2 hours. The mixture was diluted with EtOAc (75 mL) and washed 3 times with water (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow solid (6.69 g, 86%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 7.42-7.45 (q, 1H), 7.94-7.97 (m, 1H), 8.30-8.32 (m, 1H)
LCMS Rt = 1.38 min, MS m / z 240 [MH] ⁺ .

Preparation Example 48
3-chloro-2-cyclopropylpyridine

3-Chloro-2-bromopyridine (5.0 g, 26 mmol) and tribasic potassium phosphate (19.3 g, 90.9 mol) were suspended in toluene (40.0 mL) and water (2.0 mL). The mixture was sonicated for 10 minutes before cyclopropylboronic acid (1.12 g, 13.0 mmol), palladium (II) acetate (0.093 g, 0.414 mol) and tricyclohexylphosphine (0.243 g, 0.867 mol). ) Was added to the reaction mixture, which was heated in a preheated DrySyn® at 100 ° C. for 2 hours in a nitrogen atmosphere. Then cyclopropylboronic acid (1.12 g, 13.0 mmol), palladium (II) acetate (0.093 g, 0.41 mol) and tricyclohexylphosphine (0.243 g, 0.87 mol) are added to the reaction mixture, The mixture was stirred for 2 hours. Then cyclopropylboronic acid (1.12 g, 13.0 mmol), palladium (II) acetate (0.093 g, 0.41 mol) and tricyclohexylphosphine (0.243 g, 0.87 mol) are added to the reaction mixture, The mixture was stirred for an additional 2 hours. The reaction mixture was then kept stirring at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (40.0 mL) and water (40.0 mL) and filtered through a pad of Arbocel® in a stream of nitrogen. The organic layer was separated and washed with 10% aqueous citric acid (3 × 25.0 mL) and then with aqueous hydrochloric acid (1.0 M, 3 × 20.0 mL). The organic layer was discarded, and a saturated aqueous sodium hydrogen carbonate solution (100.0 mL) was carefully added to the aqueous layer to make it basic again. The product was extracted with tert-butyl methyl ether (3 × 20.0 mL). The combined organics were washed once more with 10% aqueous citric acid (25.0 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a light brown oil (2.45 g, 62%).
¹ H NMR (400 MHz, d ₆ -DMSO): δ 0.94-1.01 (m, 4H), 2.40-2.48 (m, 1H), 7.13-7.16 (m, 1H), 7.78-7.81 (m, 1H), 8.33-8.34 (m, 1H).
LCMS Rt = 2.27 min, MS m / z 154 [MH] ⁺ .

Preparation Example 49
3-chloro-2-isobutylpyridine

3-chloro-2-iodopyridine (1.552 g, 6.482 mmol), isobutylboronic acid (0.725 g, 7.112 mmol), potassium carbonate (2.7 g, 0.0195 mol) and silver oxide (3.8 g, 0.0164 mol) was suspended in THF (25 mL). The mixture was degassed three times and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane (1: 1) (0.520 g, 0.637 mmol) was added. The reaction mixture was heated at 75 ° C. under nitrogen for 7 hours. The mixture was diluted with EtOAc (15 mL) and washed with aqueous hydrochloric acid (2.0 M, 2 × 15 mL). The organic layer was discarded, and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was carefully added to the aqueous layer to make it basic. The product was extracted with EtOAc (2 × 15 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0-5% EtOAc / heptane to give the title compound as a colorless oil (0.582 g, 53% yield).
¹ H NMR (400 MHz, d ₆ -DMSO): δ 0.87-0.89 (d, 6H), 2.09-2.17 (m, 1H), 2.72-2.74 (d, 2H), 7.24-7.27 (m, 1H), 7.83-7.86 (m, 1H), 8.44-8.45 (m, 1H).
LCMS Rt = 1.30 min, MS m / z 170 [MH] ⁺ .

Preparation Example 50
2-tert-butyl-3-chloropyridine

2,3-dichloropyridine (1.0 g, 0.0068 mol) and copper iodide (0.065 g, 0.341 mmol) were dissolved in THF (6 mL). The mixture was degassed three times and then cooled to 0 ° C. with an ice bath. A solution of tert-butyl (chloro) magnesium in diethyl ether (5.10 mL, 0.0102 mol) was then added dropwise to the reaction mixture in nitrogen while maintaining the temperature at 0 ° C. with an ice bath. When the addition was complete, it was allowed to warm to room temperature for 16 hours. Saturated aqueous sodium chloride solution was slowly added to the reaction mixture (20 mL). The product was then extracted with tert-butyl methyl ether (20 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0-5% EtOAc / heptane to give the title compound as a yellow oil (0.108 g, 9% yield).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.51 (s, 3H), 7.07-7.10 (m, 1H), 7.61-7.63 (m, 1H), 8.42-8.44 (m, 1H).
LCMS Rt = 1.55 min, MS m / z 170 [MH] ⁺ .

Preparation Example 51
5-Chloro-6- (1-hydroxy-1-methylethyl) pyridin-3-ol

1- (3-Chloro-5-hydroxypyridin-2-yl) ethanone (0.075 g, 0.0068 mol) was dissolved in THF (2 mL). The mixture was degassed three times and then cooled to 0 ° C. with an ice bath. A solution of bromo (methyl) magnesium in diethyl ether (0.3 mL, 0.0009 mol) was then added dropwise to the reaction mixture in nitrogen while maintaining the temperature at 0 ° C. with an ice bath. When the addition was complete, it was allowed to warm to room temperature for 16 hours. Then, a solution of bromo (methyl) magnesium in diethyl ether (0.3 mL, 0.0009 mol) was added dropwise to the reaction mixture, and the mixture was further stirred at room temperature for 3 hours. Saturated aqueous sodium chloride solution was slowly added to the reaction mixture (10 mL) before it was extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a translucent solid (0.049 g, 4% yield):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.50 (s, 6H), 2.31 (s, 3H), 5.30 (s, 1H), 7.24-7.25 (d, 1H), 8.00-8.01 (d, 1H) .
LCMS Rt = 0.81 min, MS m / z 188 [MH] ⁺ .

Preparation Example 52
3,4,6-trifluoro-2-methoxybenzaldehyde

Paraformaldehyde (0.960 g, 0.01066 mol) and magnesium dichloride (0.505 g, 0.005304 mol) were suspended in THF (10.0 mL). Triethylamine (0.75 mL, 0.0054 mol) was added and the mixture was stirred in nitrogen for 10 minutes. 2,3,5-trifluorophenol (0.524 g, 0.00027 mol) was then added and the reaction mixture was stirred at reflux for 16 hours. The reaction mixture was filtered and the filtrate was diluted with aqueous hydrochloric acid (2.0 M, 15 mL). The product was then extracted with tert-butyl methyl ether (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was dissolved in DMF (5.0 mL). Potassium carbonate (0.55 g, 0.003979 mol) and methyl iodide (0.175 mL, 0.00072 mol) were then added to the mixture, which was stirred at 50 ° C. for 3 hours in nitrogen, then at room temperature. Stirring continued for hours. The reaction system was diluted with a saturated saline solution (15 mL), and extracted with tert-butyl methyl ether (20 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0-10% EtOAc / heptane to give the title compound as a colorless oil (0.080 g, 0.432 mmol).
¹ H NMR (400 MHz, CDCl ₃ ): δ 4.14-4.15 (d, 3H), 6.68-6.74 (m, 1H), 10.27 (m, 1H).
LCMS Rt = 1.07 min.

Preparation Example 53
3-Chloro-2- (1,1-difluoro-2-methylpropyl) pyridine

N-ethyl-N- (trifluoro-λ-4-sulfanyl) ethanamine (5.29 mL, 0.040 mol) was converted to 1- (3-chloropyridin-2-yl) -2-methylpropan-1-one ( 0.74 g, 4.4 mmol) in DCM (20 mL) was added dropwise in a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 240 hours. DCM, then saturated brine solution (3 mL) and water (5 mL) were added to the reaction mixture (10 mL). The aqueous layer was further extracted with DCM (2 × 15 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0-10% EtOAc / heptane to give the title compound as a brown oil (0.803 g, 44% yield).
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.06-1.07 (d, 6H), 2.74-2.90 (m, 1H), 7.32-7.35 (m, 1H), 7.77-7.80 (m, 1H), 8.50- 8.53 (m, 1H).

Preparation Example 54
1- (3-Chloropyridin-2-yl) -2-methylpropan-1-one

Chloro (isopropyl) magnesium in THF (35.0 mL, 0.070 mol) was added dropwise to a solution of chloro-2-pyridinecarbonitrile (5.01 g, 0.036 mol) in THF (100 mL) at 0 ° C. in a nitrogen atmosphere. did. After the addition was complete, it was maintained at 0 ° C. for 2 hours. The reaction mixture was placed in ice (100 g) and acidified with aqueous hydrochloric acid (2.0 M, 100 mL) to pH = 3. The product was then extracted with EtOAc (3 × 100 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 3-10% EtOAc / heptane to give the title compound as a yellow oil (1.98 g, 15% yield):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.18 (d, 6H), 3.70 (m, 1H), 7.34 (m, 1H), 7.78 (m, 1H), 8.52 (m, 1H).
LCMS Rt = 2.89 min, MS m / z 184 [MH] ⁺ .

Preparation Example 55
3-Chloro-2- (1,1-difluoroethyl) pyridine

Prepared according to Preparation 53 using 1- (3-chloropyridin-2-yl) ethanone:
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.04-2.13 (t, 3H), 7.32-7.34 (m, 1H), 7.78-7.81 (m, 1H), 8.49-8.51 (m, 1H).
LCMS Rt = 1.24 min, MS m / z 178 [MH] ⁺ .

Preparation Example 56
Cyclopropanol

Aqueous H ₂ O ₂ (30%, 20 mL, ₂₀₀ mmol) was added dropwise at 0 ° C. to a suspension of cyclopropylboronic acid (0.62 g, 7.2 mmol) in 10% aqueous NaOH (5 mL) with continuous stirring. did. The resulting mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with Et ₂ O. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo at 0 ° C. This material was dissolved in Et ₂ O (15 mL) and 4 Å molecular sieves were added, which was kept overnight at room temperature to give the title compound as a pale yellow oil (140 mg, 33%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.43 (m, 4 H), 3.36 (m, 1 H).

Preparation Example 57
3-Chloro-2- (difluoromethoxy) pyridine

2-Hydroxypyridine (1.0 g, 7.7 mmol) was slowly added to a dry acetonitrile suspension of NaH (0.34 g, 8.5 mmol) in a nitrogen atmosphere at room temperature and stirred for 10 minutes. Cesium fluoride (0.12 g, 0.77 mmol) was then added followed by the slow addition of difluoro (fluorosulfonyl) trimethylsilyl acetate (1.7 mL, 2.1 g, 8.5 mmol). The reaction mixture was quenched with water and most of the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (1.3 g, 94% yield):
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.09 (d, 1H), 7.48 (t, 1H), 7.78 (d, 1H), 8.10 (d, 1H).
LCMS Rt = 1.37 min, MS m / z 180 [MH] ⁺ .

Preparation Example 58
6-d9-tert-butoxy-5-chloropyridin-3-ol

Hydrogen peroxide solution (30%, 0.462 mL, 4.52 mmol) was added to 2-tert-butoxy-3-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) pyridine-d9 (Preparation 112, 1.21 g, 3.773 mmol) in MeOH / H ₂ O (30 mL: 10 mL) was added in 5 portions at 0 ° C. The reaction mixture was stirred at room temperature for 3.5 hours. Aqueous sodium thiosulfate (0.1 M, 20 mL) was added, followed by stirring at room temperature for 5 minutes and extraction with 50 mL of EtOAc. The organics were washed with brine (2 × 30 mL), dried over magnesium sulfate and evaporated in vacuo to give the crude material as a yellow oil. The crude material was purified by silica gel chromatography eluting with 0-60% EtOAc / heptane to give the title compound as a waxy white solid:
¹ H NMR (400 MHz, CDCl ₃ ): δ 4.73 (s, OH), 7.24 (d, 1H), 7.69 (d, 1H).
LCMS Rt = 1.27 min, MS m / z 209 [MH] ^- .

Preparation Example 59
Tert-Butyl 5-chloro-2,4-difluorobenzoate

Di-tert-butyl dicarbonate (22.7 g, 104 mmol) and then N, N-dimethylpyridin-4-amine (0.635 g, 5.20 mmol) were added to 5-chloro-2,4-difluorobenzoic acid (10 0.0 g, 51.9 mmol) in tert-butanol (140.0 mL) was added in several portions. The mixture was stirred at 45 ° C. under nitrogen for 64 hours. After the solvent was concentrated in vacuo, EtOAc (50.0 mL) was added. The mixture was washed with aqueous hydrochloric acid (1.0 M, 50.0 mL), then saturated aqueous sodium hydroxide (1.0 M, 50.0 mL), and finally with brine (50.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was filtered through a pad of silica eluting with a 30% EtOAc / heptane solution to give the title compound as a colorless oil (11.6 g, 90%):
¹ H NMR (400 MHz, d ⁶ -DMSO): δ 1.50 (s, 9H), 7.62-7.67 (m, 1H), 7.94-7.98 (m, 1H).
LCMS Rt = 2.98 min.

Preparation Example 60
Tert-Butyl 2,4-difluorobenzoate

2,4-Difluorobenzoic acid (1 g, 6.32 mmol), di-tert-butyl carbonate (2.76 g, 12.65 mmol) and 4-dimethylaminopyridine (77 mg, 0.63 mmol) in tert-butanol (10 mL) The solution was heated to 40 ° C. for 18 hours. The reaction was quenched with 2M aqueous HCl and extracted with EtOAc. The combined organics were washed with NaOH solution (1M) and evaporated to give the title compound as a yellow oil (1.1 g, 81%):
¹ H NMR (400 MHz, CD ₃ OD): δ 1.57 (s, 9H), 6.95-7.03 (m, 2H), 7.82-7.91 (m, 1H).
LCMS Rt = 3.14 min, no molecular ions were observed.

Preparation Example 61
Tert-Butyl 3,4,5-trifluorobenzoate

To a tBuOH solution (10 mL) was added 3,4,5-trifluorobenzoic acid (1.00 g, 5.67 mmol), 4-dimethylaminopyridine (70 mg, 0.57 mmol), and then di-tert-butyl carbonate (2. 48 g, 11.35 mmol) was added. The reaction mixture was heated at 40 ° C. for 18 h, quenched with 1M aqueous HCl and extracted with EtOAc. The combined organics were dried and concentrated in vacuo to give the title compound as a colorless oil (1.31 g, 100%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.56 (s, 9H), 7.60 (t, 2H).
LCMS Rt = 3.59 min, no molecular ions were observed.

Preparation Example 62
4-[(5-Chloro-6-isopropoxypyridin-3-yl) oxy] -3,5-difluorobenzoic acid

4-[(5-Chloro-6-isopropoxypyridin-3-yl) oxy] -3,5-difluorobenzoate (Preparation 145, 426 mg, 1.06 mmol) and LiOH (100 mg) were added in THF. : Added to water (1: 1) solution and heated at 50 ° C for 3 hours. The reaction was then quenched with 1M aqueous HCl and extracted with EtOAc. The combined organics were dried and concentrated in vacuo to give the title compound as a white solid (342 mg, 94% yield):
¹ H NMR (400 MHz, CD ₃ OD): δ 1.33 (d, 6H), 5.25 (m, 1H), 7.52 (s, 1H), 7.76 (d, 2H), 7.81 (s, 1H).
LCMS Rt = 3.59 min, MS m / z 344 [MH] ⁺ .

Preparation Example 63
Tert-Butyl 2,4,6-trifluorobenzoate

Di-tert-butyl carbonate (4.95 g, 22.7 mmol) was added to 2,4,6-trifluorobenzoic acid (2.0 g, 11.3 mmol) and 4-dimethylaminopyridine (139 mg, 1.14 mmol). To the tBuOH (30 mL) solution was added and the reaction mixture was heated at 40 ° C. for 18 hours. The reaction mixture was then quenched with 1M aqueous HCl and extracted with EtOAc. The combined organics were washed with 1M aqueous NaOH then brine, dried and concentrated in vacuo to give the title compound as a pale yellow oil (2.63 g, 52% yield):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.58 (s, 9H), 6.67 (t, 2H).
LCMS Rt = 3.16 min, no molecular ions were observed.

Preparation Example 64
2,3,4,6-tetrafluorobenzoic acid

(2,3,4,6-tetrafluorophenyl) methanol (1.50 g, 8.33 mmol), sodium periodate (8.91 g, 41.6 mmol) and ruthenium (III) chloride (345 mg, 1.67 mmol) Was added to a mixture of MeCN (20 mL), water (10 mL) and carbon tetrachloride (20 mL). The reaction was stirred at room temperature for 6 hours, then filtered through arbocel (EtOAc as eluent) and the filtrate evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with EtOAc to give the title compound as a colorless oil (1.60 g, 99% yield):
¹ H NMR (400 MHz, CD ₃ OD): δ 5.06 (m, 1H).
LCMS Rt = 1.74 min, no molecular ions were observed.

Preparation Example 65
Tert-Butyl 2,3,4,6-tetrafluorobenzoate

Di-tert-butyl carbonate (3.63 g, 16.7 mmol) was added to 2,3,4,6-tetrafluorobenzoic acid (1.60 g, 8.88 mmol), 4-dimethylaminopyridine (102 mg, 0.83 mmol). ) In tBuOH (20 mL) and heated at 40 ° C. for 16 h. The reaction mixture was quenched with 1M aqueous HCl and extracted with EtOAc. The combined organics were washed with 1M aqueous NaOH followed by brine and evaporated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 50% EtOAc / heptane to give the title compound as a colorless oil (1.25 g, 59% yield):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.57 (s, 9H), 6.73-6.85 (m, 1H).
LCMS Rt = 3.84 min, no molecular ions were observed.

Preparation Example 66
3-chloro-2-d7-isopropoxypyridine

d ⁸ -Isopropyl alcohol (4.71 mL, 61.5 mmol) in anhydrous THF (10 mL) was added to a suspension of NaH (60% mineral oil) (2.46 g, 61.5 mmol) in anhydrous THF (50 mL). Slowly added over minutes. After 10 minutes, a solution of 2-fluoro-3-chloropyridine (5.05 g, 38.4 mmol) in THF (10 mL) was added at 5 ° C. (ice bath) over 5 minutes. The reaction was then warmed to room temperature and stirred for 18 hours. The reaction was diluted with THF (20 mL), cooled to 5 ° C. (ice bath), and quenched with water (50 mL). The mixture was extracted with EtOAc (50 mL). Brine was added to aid separation. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude oil which was purified by silica gel chromatography eluting with 0-30% EtOAc / heptane to give the title compound as a colorless Obtained as an oil (5.37 g, 53% yield):
¹ H NMR (400 MHz, CDCl ₃ ): δ 6.78-6.81 (m, 1H), 7.60-7.62 (m, 1H), 8.03-8.04 (m, 1H).
LCMS Rt = 1.41 min, no molecular ions were observed.

Preparation Example 67
4- (5-Chloro-6-fluoropyridin-3-yloxy) -2,5-difluorobenzoic acid p-tolyl

Potassium carbonate (1.40 g, 10.14 mmol) was added to 4-methylphenyl 2,4,5-trifluorobenzoate (Preparation Example 12, 1.80 g, 6.76 mmol), 5-chloro-6-fluoropyridine- 3-ol (1.05 g, 7.10 mmol) in DMSO was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (2 × 25 mL), the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The remaining crude product was then purified by silica gel chromatography eluting with 10-50% EtOAc / heptane to give the title compound (1.48 g, 56%):
¹ H NMR (d ₆ -DMSO): δ 2.30 (m, 3H), 7.15 (m, 2H), 7.30 (m, 2H), 7.40 (m, 1H), 8.10 (m, 1H), 8.25 (m, 1H), 8.35 (m, 1H).
LCMS Rt = 5.05 min, no molecular ions were observed.

Preparation Example 68
N- (sec-butylsulfonyl) -2,4,5-trifluorobenzamide

N- [3- (dimethylamino) propyl] -N′-ethylcarbodiimide hydrochloride (0.41 g, 2.1 mmol), 4-dimethylaminopyridine (0.26 g, 2.1 mmol) and N-ethyl-N— Isopropylpropan-2-amine (0.9 mL, 4.2 mmol) was added to a solution of 2,4,5-trifluorobenzoic acid (0.25 g, 1.4 mmol) in DCM. After 10 minutes, butane-2-sulfonamide (Preparation Example 29, 0.29 g, 2.1 mmol) was added and the reaction was maintained at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound as a white solid (0.19 g, 31% yield):
¹ H NMR (400 MHz; d ₆ -DMSO): δ 1.0 (m, 3H), 1.3 (s, 3H), 1.6 (m, 1H), 1.9 (m, 1H), 3.5 (m, 1H), 7.7 (m, 1H), 7.8 (m, 1H).
LCMS Rt = 2.26 min, MS m / z 294 [MH] ^- .

Preparation Example 69
5-chloro-6-cyclopropylpyridin-3-ol

A round bottom flask was charged with 3-chloro-2-cyclopropylpyridine (Preparation 48, 0.475 g, 3.092 mmol), bis (pinacolato) diboron (0.980 g, 3.859 mol) and 4,4-di-tert. -A solution of butyl-2,2-dipyridyl (0.025 g, 0.093 mmol) in heptane (1.55 L) was charged. The reaction mixture was circulated 6 times between vacuum and nitrogen over 15 minutes. Then, di-μ-methanolatodiiridium (Ir-Ir) -cycloocta-1,5-diene (1: 2) (0.063 g, 0.093 mmol) was added, and the reaction was carried out at room temperature in a nitrogen atmosphere. For 18 hours. The reaction mixture was evaporated to dryness to give a red viscous oil. The resulting oil was dissolved in acetone (10.0 mL) and cooled to 0 ° C. with an ice bath. A solution of potassium peroxymonosulfate (2.55 g, 4.15 mmol) in water (10.0 mL) was then added dropwise to the mixture and stirred at this temperature for 1 hour. The reaction was then diluted with tert-butyl methyl ether (25.0 mL) and washed with brine (3 × 25.0 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0-30% EtOAc / heptane to give the title compound as a pale yellow solid (0.220 g, 1.28 mmol, 42%). :
¹ H NMR (400 MHz, d ₆ -DMSO): δ 0.81-0.85 (m, 2H), 0.86-0.91 (m, 2H), 2.26-2.32 (m, 1H), 7.19 (d, 1H), 7.94- 7.95 (d, 1H), 10.05 (s, 1H).
LCMS Rt = 1.85 min, MS m / z 170 [MH] ⁺ .

Preparation Example 70
5-chloro-4-[(5-chloro-6-cyclopropylpyridin-3-yl) oxy] -2-fluorobenzoic acid 4-methylphenyl

4-methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation Example 26, 0.330 g, 1.168 mmol) was added to 5-chloro-6-cyclopropylpyridin-3-ol (Preparation Example 69, 0.00). 214 g, 1.262 mmol) and potassium carbonate (0.32 g, 2.315 mmol) in DMSO (5.0 mL) was added in several portions over 5 minutes. The mixture was stirred at room temperature for 3 hours and then partitioned between water (20.0 mL) and tert-butyl methyl ether (20.0 mL). The organic layer was further washed with water (2 × 20.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0-5% EtOAc / heptane to give the title compound as a white solid (0.289 g, 0.668 mmol, 57%). :
¹ H NMR (400 MHz, d ₆ -DMSO): δ 0.97-1.00 (m, 2H), 1.00-1.07 (m, 2H), 2.32 (s, 3H), 2.44-2.50 (m, 1H), 7.13- 7.17 (m, 2H), 7.22-7.27 (m, 2H), 7.28-7.32 (m, 1H), 7.89 (d, 1H), 8.23 (d, 1H), 8.37 (d, 1H).
LCMS Rt = 3.60 min, MS m / z 432 [MH] ⁺ .

Preparation Example 71
5-chloro-4-{[5-chloro-6- (2,2,3,3-tetrafluoropropoxy) pyridin-3-yl] oxy} -2-fluorobenzoate tert-butyl

Potassium carbonate (3.02 g, 21.85 mmol) was added to tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 59, 2.26 g, 9.09 mmol), 5-chloro-6- (2, 2,3,3-Tetrafluoropropoxy) pyridin-3-ol (Preparation Example 73, 2.25 g, 8.67 mmol) was added in several portions to a DMSO (13.5 mL) suspension. The mixture was stirred at room temperature under nitrogen for 3 hours. Tert-butyl methyl ether (50.0 mL) was added and the mixture was washed with water (3 × 50.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was suspended in heptane (20.0 mL) and concentrated in vacuo. The resulting solid was suspended in heptane (20.0 mL) and heated to 90 ° C. until completely dissolved. The mixture was cooled with stirring and the remaining solid was collected by filtration. The filtrate was concentrated in vacuo and the resulting solid was suspended in heptane (10.0 mL) and heated to 90 ° C. until dissolved. The mixture was cooled again with stirring and the remaining solid was collected by filtration. The two recoveries were combined to give the title compound as a white solid (2.58 g, 5.29 mmol, 61%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 1.52 (s, 9H), 4.93 (t, 2H), 6.50-6.78 (m, 1H), 7.08 (d, 1H), 7.95 (d, 1H) , 8.08-8.14 (m, 2H).
LCMS Rt = 3.41 min, MS m / z 522 [MH] ⁺ .

Preparation Example 72
5-chloro-4-{[5-chloro-6- (1,1,3,3-tetrafluoropropoxy) pyridin-3-yl] oxy} -2-fluorobenzoic acid

Trifluoroacetic acid (5.0 mL) was added to 5-chloro-4-{[5-chloro-6- (2,2,3,3-tetrafluoropropoxy) pyridin-3-yl] oxy} -2-fluorobenzoate. To a solution of tert-butyl acid (Preparation Example 71, 2.56 g, 5.24 mmol) in DCM (5.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and then diluted with EtOAc (30.0 mL). The organic layer was washed with aqueous hydrochloric acid (2 × 15.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. This oil was dissolved in heptane (20.0 mL) and stirred at reflux for 2 hours, then allowed to cool to room temperature. The title compound was isolated as a white solid by filtration (1.98 g, 4.58 mmol, 87%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 4.93 (t, 2H), 6.50-6.78 (m, 1H), 7.05 (d, 1H), 7.99 (d, 1H), 8.10-8.15 (m, 2H).
LCMS Rt = 2.63 min, MS m / z 432 [MH] ⁺ .

Preparation Example 73
5-Chloro-6- (2,2,3,3-tetrafluoropropoxy) pyridin-3-ol

Hydrogen peroxide solution (30% aqueous solution, 30.2 mL, 0.26 mol) was added to 3-chloro-2- (2,2,3,3-tetrafluoropropoxy) -5- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (Preparation Example 74, 81.0 g, 0.22 mol) was added to a methanol (500 mL) solution at 0 ° C., and the reaction system was left to room temperature. Warmed and stirred for 4 hours. The reaction mixture was quenched with 10% sodium thiosulfate solution (100 mL) and the methanol was removed in vacuo. The resulting mixture was extracted with EtOAc (2 × 250 mL) and the combined organics were separated, dried over magnesium sulfate, filtered and evaporated to give a yellow oil. The oil was purified by silica gel chromatography eluting with 10% EtOAc / heptane to give the title compound as a viscous colorless oil (46.7 g, 82%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 4.60 (t, 2H), 5.60 (br, 1H), 5.95-6.20 (m, 1H), 7.36 (s, 1H), 7.70 (s, 1H).
LCMS Rt = 2.43 min, MS m / z 257 [MH] ^- .

Preparation Example 74
3-Chloro-2- (2,2,3,3-tetrafluoropropoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine

A three-necked flask was charged with 3-chloro-2- (2,2,3,3-tetrafluoropropoxy) pyridine (Preparation Example 75, 71.0, 0.3 mol) and heptane (350 mL). The mixture was circulated 3 times between nitrogen and vacuum. Bispinacolatodiboron (74.0 g, 0.3 mol) and di-tert-butyldipyridyl (4.70 g, 17.5 mmol) were then added and the mixture was degassed again and maintained in a nitrogen atmosphere. Di-μ-methanolatodiiridium (Ir-Ir) -cycloocta-1,5-diene (1: 2) (6.00 g, 9.05 mmol) was then added and the resulting mixture was stirred at room temperature for 16 hours. Stir. The reaction mixture was then cooled to 0 ° C., MeOH (70 mL) was added dropwise, then concentrated in vacuo, and the resulting mixture was partitioned between EtOAc (500 mL) and water (300 mL). The organic layer was separated, dried over magnesium sulfate, filtered and evaporated to give a brown oil. The oil was purified by silica gel chromatography eluting with 0-10% EtOAc / heptane to give the title compound as a colorless oil (81 g, 75%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.36 (s, 12H), 4.82 (t, 2H), 5.95-6.23 (m, 1H), 8.05 (s, 1H), 8.40 (s, 1H).
MS m / z 370 [M] ⁺ .

Preparation Example 75
3-Chloro-2- (2,2,3,3-tetrafluoropropoxy) pyridine

2,2,3,3-Tetrafluoropropan-1-ol (60.0 g, 0.45 mol) was added to an anhydrous THF (450 mL) slurry of NaH (60% oil dispersion, 15.20 g, 0.63 mol). It was added at 0 ° C. and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. 2,3-Dichloropyridine (45.0 g, 0.30 mol) was added and the reaction was heated to gentle reflux for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between EtOAc (300 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give the title compound as a yellow oil (71 g, 96%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 4.75 (t, 2H), 5.95-6.2 (m, 1H), 6.95 (m, 1H), 7.65 (m, 1H), 8.12 (m, 1H).
LCMS Rt = 3.07 min, no molecular ion was visible.

  The following compounds were prepared according to the method described for Preparation 15 using appropriate reagents and conditions.

  The following compounds were prepared by methods analogous to those described for Preparation 44.

  The following compounds were prepared by methods analogous to those described for Preparation 58.

  The following compounds were prepared by the method described for Preparation 14 using the appropriate reagents and conditions.

  The following compounds were prepared using the appropriate reagents and conditions according to the method described for Preparation 13 above.

  The following compounds were prepared by the method described for Preparation Example 7, using appropriate reagents and conditions.

  The following compounds were prepared using the appropriate reagents and conditions according to the method described for Preparation 8.

  The following compounds were prepared by the method described for Preparation 22 using the appropriate reagents and conditions.

  The following compounds were prepared by the method described for Preparation 9 using appropriate reagents and conditions.

  The following compounds were prepared by the method described for Preparation 36 using appropriate reagents and conditions.

  The following compounds were prepared by the method described for Preparation 31 using appropriate reagents and conditions.

  The following compounds were prepared by the method described for Preparation 32 using appropriate reagents and conditions.

  The following compounds were prepared by the method described for Preparation 33 using appropriate reagents and conditions.

  The following compounds were prepared by the method described for Preparation 38 using the appropriate reagents and conditions.

  The following compounds were prepared by the method described for Preparation 37 using appropriate reagents and conditions.

Preparation Example 216
3-Difluoromethoxy-2-cyclopropylpyridine

Prepared according to Preparation 48 using 3-difluoromethoxy-2-bromopyridine (Preparation Example 217) and cyclopropylboronic acid. The reaction system was heated to 95 ° C. for 18 hours, cooled to room temperature, and filtered through arbocel. The filtrate was concentrated in vacuo and purified using silica gel column chromatography eluting with ethyl acetate: heptane (1: 5) to give the title compound as a colorless oil (273 mg, 58%).
¹ H NMR (400 MHz; d ₆ -DMSO): δ 0.95 (m, 4H), 2.3 (m, 1H), 7.05-7.42 (t, 1H), 7.15 (m, 1H), 7.5 (m, 1H) , 8.25 (m, 1H).
LCMS Rt = 2.09 min, MS m / z 186 [MH] ⁺ .

Preparation Example 217
3-difluoromethoxy-2-bromopyridine

To a solution of 2-bromo-3-pyridinol (1.26 g, 7.23 mmol) in DMF (35 mL) and water (5 mL) was added sodium chlorodifluoroacetate (2.93 g, 18.1 mmol) followed by cesium carbonate (4. 71 g, 14.5 mmol) was added. The reaction was heated to 100 ° C. for 36 hours and then partitioned between EtOAc and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc: heptane (1: 3) to give the title compound as a colorless oil (570 mg, 35%).
¹ H NMR (400 MHz; d ₆ -DMSO): δ 7.15-7.55 (t, 1H), 7.55 (m, 1H), 7.80 (m, 1H), 8.25 (m, 1H).
LCMS Rt = 1.91 min, MS m / z 226 [MH] ⁺ .

Preparation Example 218
Tert-Butyl 2,5-dichloro-4-fluorobenzoate

Di-tert-butyl dicarbonate (940 mg, 4.31 mmol) was added to 2,5-dichloro-4-fluorobenzoic acid (J. Med. Chem., 1972, 15, p79, 300 mg, 1.44 mmol) and dimethylamino. Pyridine (35 mg, 0.29 mmol) was added to a solution of tert-butyl alcohol (10 mL). The reaction mixture was stirred at 40 ° C. for 24 hours, then diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography eluting with heptane: dichloromethane (95: 5-60: 40) to give the title compound as a pale yellow oil (251 mg, 66%, expected compound) : 5.5: 1 mixture of starting materials).
LCMS Rt = 3.19 min, no mass ions.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.52 (s, 9H), 7.15 (d, 1H), 7.77 (d, 1H).

Preparation Example 219
Tert-Butyl 2,5-dichloro-4- (5-chloro-6-cyclopropylpyridin-3-yloxy) benzoate

Tert-butyl 2,5-dichloro-4-fluorobenzoate (Preparation Example 218, 251 mg, 0.61 mmol) was added to 5-chloro-6-cyclopropylpyridin-3-ol (Preparation Example 69, 161 mg, 0.61 mmol). ) And potassium carbonate (393 mg, 1.82 mmol) in dimethyl sulfoxide (5 mL). The reaction mixture was stirred at room temperature for 18 hours, then diluted with sodium hydroxide (1M, 5 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography eluting with heptane: dichloromethane (95: 5-60: 40) to give the title compound as a colorless oil (116 mg, 30%).
LCMS Rt = 4.54min, MS m / z 416 [MH] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 0.96-1.03 (m, 4H), 1.53 (s, 9H), 2.39-2.46 (m, 1H), 6.85 (s, 1H), 7.21 (d, 1H) , 7.84 (s, 1H), 8.08 (d, 1H).

Preparation Example 220
2,5-dichloro-4- (5-chloro-6-cyclopropylpyridin-3-yloxy) benzoic acid

Trifluoroacetic acid (42 μL, 0.56 mmol) was added to tert-butyl 2,5-dichloro-4- (5-chloro-6-cyclopropylpyridin-3-yloxy) benzoate (Preparation Example 219, 116 mg, 0.28 mmol). ) In dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was dissolved in methanol (10 mL) and then concentrated in vacuo to give the title compound as a colorless solid (100 mg, 100%).
LCMS (8 min acidic experiment) Rt = 3.79 min, MS m / z 360 [MH] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 0.95-0.98 (m, 2H), 1.00-1.04 (m, 2H), 2.43-2.47 (m, 1H), 7.26 (s, 1H), 7.80 (d, 1H), 8.01 (s, 1H), 8.30 (d, 1H).

Preparation Example 221
3-Chloro-2-cyclopropyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine

3-Chloro-2-cyclopropylpyridine (Preparation 48, 70 mg, 0.46 mmol) and bis (pinacolato) diboron (105 mg, 0.41 mmol) were added to dioxane (100 mL). The solution was degassed by bubbling N ₂ for 30 minutes. The solution was heated to 80 ° C. and 4,4-di-tert-butyl-2,2-dipyridyl (2.4 mg, 0.009 mmol) + cyclooctadiene (dimethoxy) iridium (I) dimer (3. 0 mg, 0.005 mmol) was added. The flask was degassed with N ₂ (× 3) and stirred at 80 ° C. for 18 hours. The reaction was cooled in an ice bath, quenched by slow addition of methanol (20 mL) and concentrated to dryness to give a reddish brown oil. This material was purified by silica gel column chromatography eluting with 2: 1 heptane: ethyl acetate to give the title compound as a colorless oil (32 mg, 25%).
LCMS Rt = 2.26 min, no mass ions were observed.
¹ HNMR (400 MHz, CDCl ₃ ): δ 0.98-1.28 (m, 4H), 1.30 (s, 12H), 2.47-2.58 (m, 1H), 7.94 (s, 1H), 8.61 (s, 1H).

Preparation Example 222
Trichloromethanesulfonic acid 5-chloro-6-isopropoxypyridin-3-yl

To a stirred ice-cold solution of 5-chloro-6-isopropoxypyridin-3-ol (Preparative Example 15, 1050 mg, 3.37 mmol) and triethylamine (356 mg, 0.49 mL, 3.52 mmol) in DCM (10 mL) was added N- Phenyltrifluoromethanesulfonimide (633 mg, 2.93 mmol) was added in several portions over 10 minutes. The reaction mixture was allowed to warm to room temperature for 18 hours, then washed with 1M NaOH solution (2 × 5 mL), water (5 mL), dried over MgSO ₄ , filtered and evaporated to give the title compound (895 mg, 95%) was obtained as a clear oil.
LCMS Rt = 2.93 min, MS m / z 278 [M-iPrH] ^+
1 HNMR (400 MHz, CDCl ₃ ): δ 1.38 (d, 6H), 5.28-5.40 (m, 1H), 7.60 (s, 1H), 8.03 (s, 1H).

Preparation Example 223
5-chloro-6-isopropoxy-3-triisopropylsilylthiopyridine

A toluene (6 mL) mixture of 5-chloro-6-isopropoxypyridin-3-yl trifluoromethanesulfonate (Preparation 222, 361 mg, 1.13 mmol) and cesium carbonate (515 mg, 1.58 mmol) was bubbled with nitrogen. After stirring for 5 minutes, triisopropylsilylthiol (344 mg, 0.388 mL, 1.81 mmol) as a toluene (2 mL) solution, then (1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium (II): dichloromethane A complex with (138 mg, 0.169 mmol) was added. The resulting mixture was refluxed in nitrogen for 18 hours. The cooled reaction was diluted with EtOAc (10 mL) and water (10 mL). The organic layer was separated, washed with saturated brine solution (10 mL), dried over MgSO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography using EtOAc / pentane as eluent (0: 100-5 / 95) to give the title compound (422 mg, 100%) as a clear oil which was Used directly at.

Preparation Example 224
5-chloro-4-[(5-chloro-6-isopropoxypyridin-3-yl) thio] -2-fluoro-benzoic acid 4-methylphenyl

4-chlorophenyl 5-chloro-2,4-difluorobenzoate (Preparation Example 12, 275 mg, 0.97 mmol) and 5-chloro-6-isopropoxy-3-triisopropylsilylthiopyridine (Preparation Example 223, (420 mg , 1.17 mmol) to a stirred solution of DMSO (3 mL) was added potassium carbonate (269 mg, 1.95 mmol) and the resulting mixture was stirred at room temperature for 2 h before EtOAc (10 mL) and water (5 mL) were added. The organic layer was separated, washed with water (5 mL) and saturated brine solution (5 mL), dried over MgSO ₄ , filtered, evaporated and EtOAc / pentane (0/100 to 1/9). To give the title compound (352 mg, 77%) as a clear oil. This was used directly in the next step.

Preparation Example 225
2-Cyclopropyl-3- (trifluoromethyl) pyridine

2-Bromo-3-trifluoromethylpyridine (5 g, 22.1 mmol), cyclopropylboronic acid (2.09 g, 24.3 mmol), and tribasic potassium phosphate (14.1 g, 66.4 mmol) were added at high speed. Suspended in a mixture of toluene (150 mL) and water (30 mL) with stirring. The suspension was heated to 80 ° C. and N ₂ gas was bubbled directly through the suspension for 30 minutes to degas the solvent. The reaction was then heated to 95 ° C. and tricyclohexylphosphine (620 mg, 2.21 mmol) was added followed by palladium acetate (248 mg, 1.12 mmol). The reaction was kept stirring and heated at 95 ° C. for 6 hours. The reaction was cooled to room temperature, filtered through an Arbocel ™ plug and eluted with ethyl acetate. The solvent was removed to give a dark yellow oil. TBME (300 mL) was added and the organic phase was washed with 2M HCl solution (3 × 200 mL). The organic matter was discarded. TBME (300 mL) was added to the combined aqueous layers and solid sodium bicarbonate was added until the aqueous layer was pH 7. The organic layer was removed and the aqueous layer was extracted with TBME (2 × 100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 4: 1 heptane: ethyl acetate to give the title compound as a colorless oil (400 mg, 10%).
LCMS Rt = 2.77 min, MS m / z 188 [MH] ^+
1 HNMR (400 MHz, CDCl ₃ ): δ 0.96-1.08 (m, 4H), 2.28-2.38 (m, 1H), 7.08 (dd, 1H), 7.83 (d, 1H), 8.58 (d, 1H).

Preparation Example 226
5-chloro-6-phenylpyridin-3-ol

To a solution of 6-bromo-5-chloropyridin-3-ol (Preparation 239, 100 mg, 0.48 mmol) and phenylboronic acid (117 mg, 0.96 mmol) in 1,4-dioxane (5 mL) was added 2M Na _2. Aqueous CO ₃ (1 mL) and palladium tetrakistriphenylphosphine (28 mg, 0.024 mmol) were added in nitrogen. The mixture was stirred at 80 ° C. for 3.5 hours. The reaction mixture was allowed to cool to room temperature and partitioned between water and EtOAc. The desired product was present in the aqueous phase (pH: about 11). The organic phase was washed with 10 wt% aqueous NaOH (2 x 15 mL). The combined aqueous phases were neutralized with 1N aqueous citric acid and extracted with EtOAc (4 × 30 mL). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography eluting with 0-30% EtOAc / heptane to give the title compound (67 mg, 68%) as a white solid.
¹ HNMR (400 MHz, CDCl ₃ ): δ 6.33 (br s, 1H), 7.31 (d, 1H), 7.43 (m, 3H), 7.66 (m, 2H), 8.22 (d, 1H).
LCMS Rt = 2.00 min, MS m / z 206 [MH] ⁺ , 204 [MH] ⁻ .

Preparation Example 227
Tert-Butyl 3,3-difluorocyclobutanecarboxylate

3,3-Difluorocyclobutanecarboxylic acid (1.0 g, 7.3 mmol) was dissolved in DCM (10 mL) and cooled in an ice bath. To this solution was added N, N-dimethylpyridin-4-amine (92 mg, 0.735 mmol) in several portions, followed by 2-methylpropan-2-ol (1.1 g, 14.7 mmol) once. Added at. A solution of 1M N, N′-dicyclohexylcarbodiimide in DCM (8.1 mL, 8.1 mmol) was added dropwise while maintaining the temperature below 10 ° C. The resulting slurry was warmed to room temperature and stirred for 18 hours. The solid was removed by filtration and the filtrate was washed with 2N aqueous HCl (2 × 15 mL), water (2 × 15 mL), and then saturated aqueous NaHCO ₃ (2 × 15 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 1.49 g of crude product as a mixture of white solid and yellow oil. To the mixture was added pentane (30 mL) and the mixture followed by filtration through a silica gel pad eluting with pentane to give the title compound (896 mg, 63%) as a colorless oil.
¹ HNMR (400 MHz, CDCl ₃ ): δ 1.47 (s, 9H), 2.81 (m, 5H).

Preparation Example 228
3-Chloro-2- (3,3-difluorocyclobutyl) pyridine

To a solution of tert-butyl 1- (3-chloropyridin-2-yl) -3,3-difluorocyclobutanecarboxylate (Preparation Example 229, 500 mg, 1.65 mmol) in DCM (6.5 mL) was added TFA (0.50 mL). , 6.6 mmol) was added in N ₂ at room temperature. The resulting solution was stirred for 18 hours. The solvent was removed in vacuo and toluene (5 mL) was added. The resulting mixture was warmed to 90 ° C. and stirred for 18 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. The organic phase was washed with saturated aqueous NaHCO ₃ then brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product as a dark brown oil. The crude product was purified by silica gel column chromatography eluting with 0-30% EtOAc / heptane to give the title compound (271 mg, 81%) as a colorless oil.
¹ HNMR (400 MHz, CDCl ₃ ): δ 3.01 (m, 4H), 3.82 (m, 1H), 7.16 (m, 1H), 7.66 (m, 1H), 8.50 (m, 1H)
LCMS Rt = 1.26 min, MS m / z 204 [MH] ⁺ .

Preparation Example 229
Tert-Butyl 1- (3-chloropyridin-2-yl) -3,3-difluorocyclobutanecarboxylate

A solution of 3-chloro-2-fluoropyridine (500 mg, 3.8 mmol) and tert-butyl 3,3-difluorocyclobutanecarboxylate (Preparation Example 227, 877 mg, 4.6 mmol) in toluene (13 mL) was cooled to 0 ° C. did. Sodium 1,1,1,3,3,3-hexamethyldisilazane-2-id solution (1M THF solution, 5.7 mL, 5.7 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 20 minutes, then allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with 1N aqueous citric acid (3 × 15 mL) and then brine (3 × 15 mL). The organic phase is dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product as a yellow oil, which is purified by silica gel column chromatography eluting with 0-20% EtOAc / heptane. To give the title compound (505 mg, 44%) as a colorless oil.
¹ HNMR (400 MHz, CDCl ₃ ): δ 1.40 (s, 9H), 3.41 (m, 4H), 7.23 (m, 1H), 7.70 (d, 1H), 8.50 (d, 1H).
LCMS Rt = 2.85 min, no mass ions were detected.

Preparation Example 230
5-chloro-4-({5-chloro-6-[(1S) -2,2,2-trifluoro-1-methylethoxy] pyridin-3-yl} oxy) -2-methyl 4-fluorobenzoate Phenyl

5-Chloro-6-[(1S) -2,2,2-trifluoro-1-methylethoxy] pyridin-3-ol (Preparation Example 231, 60 mg, 0.25 mmol) and 5-chloro-2,4- To a mixture of 4-methylphenyl difluorobenzoate (Preparation 26, 70 mg, 0.25 mmol) in DMSO (1 mL) was added K ₂ CO ₃ (69 mg, 0.50 mmol) in N ₂ at room temperature. The mixture was stirred for 4 hours. The reaction mixture was warmed to 50 ° C. and stirred for 1 hour, then cooled to room temperature and stirred for 18 hours. The reaction was quenched with water and partitioned between water and DCM (3 × 5 mL). The mixture was filtered through a phase separation cartridge and the organic phase was washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by blowing N ₂ to give the crude product, which was purified by silica gel column chromatography eluting with 0-20% EtOAc / heptane to give the title compound (108 mg, 86%). Obtained as a colorless gum.
¹ HNMR (400 MHz, CDCl ₃ ): δ 1.58 (m, 3H), 2.39 (s, 3H), 5.77 (m, 1H), 6.66 (d, 1H), 7.11 (m, 2H), 7.23 (m, 2H), 7.54 (d, 1H), 7.93 (d, 1H), 8.24 (d, 1H).
LCMS Rt = 3.64 min, MS m / z 504 [MH] ⁺ , 502 [MH] ^- .

Preparation Example 231
5-Chloro-6-[(1S) -2,2,2-trifluoro-1-methylethoxy] pyridin-3-ol

3-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-[(1S) -2,2,2-trifluoro-1-methyl Ethoxy] pyridine (Preparation Example 232, 130 mg, 0.37 mmol) in acetone (1 mL) was stirred at 0 ° C. for 15 min with oxone® aqueous solution (1 mL, 287 mg, 0.44 mmol). It was dripped. The reaction mixture was diluted with water and extracted with DCM (3 × 5 mL). The mixture was filtered through a phase separation cartridge and the organic phase was washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by blowing N ₂ to give the crude product, which was purified by silica gel column chromatography eluting with 0-30% EtOAc / heptane to give the title compound (62 mg, 69%). Obtained as a colorless oil.
¹ HNMR (400 MHz, CDCl ₃ ): δ 1.51 (d, 3H), 5.63 (m, 1H), 7.30 (d, 1H), 7.66 (d, 1H).
LCMS Rt = 2.35 min, MS m / z 242 [MH] ⁺ , 240 [MH] ^- .

Preparation Example 232
3-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-[(1S) -2,2,2-trifluoro-1-methyl Ethoxy] pyridine

3-chloro-2-[(1S) -2,2,2-trifluoro-1-methylethoxy] pyridine (Preparation Example 233, 85 mg, 0.38 mmol), 4,4,4 ′, 4 ′, 5, 5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (115 mg, 0.45 mmol), di-μν-methanolatodiiridium (Ir-Ir) -cycloocta-1, A mixture of 5-diene (1: 2) (7.4 mg, 0.011 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridine (3 mg, 0.011 mmol) in TBME (2 mL) Heated in a wave apparatus at 80 ° C. for 30 minutes. The solvent was reduced by blowing N ₂ and the residue was filtered through a silica gel pad eluting with EtOAc (30 mL). The filtrate was concentrated in vacuo to give the title compound. This material was used in the next step without further purification.
LCMS Rt = 1.80 min, MS m / z 352 [MH] ⁺ .

Preparation Example 233
3-Chloro-2-[(1S) -2,2,2-trifluoro-1-methylethoxy] pyridine

3-Chloro-2-fluoropyridine (115 mg, 0.88 mmol) and (2S) -1,1,1-trifluoropropan-2-ol (45 wt% TBME solution, 218 mg, 0.88 mmol) in THF (1 mL) To the solution was added potassium 2-methylpropan-2-olate (120 mg, 1.05 mmol) in N ₂ at room temperature. This addition was slightly exothermic (about 40 ° C.). The resulting solution was warmed to 60 ° C. for 10 minutes. The reaction mixture was diluted with water and extracted with DCM (3 × 5 mL), and the mixture was filtered through a phase separation cartridge. The combined organic phases were washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by blowing N ₂ to give the crude product, which was purified by silica gel column chromatography eluting with 0-30% EtOAc / heptane to give the title compound (128 mg, 65%). Obtained as a colorless oil.
¹ HNMR (400 MHz, CDCl ₃ ): δ 1.55 (m, 3H), 5.81 (m, 1H), 6.93 (m, 1H), 7.69 (m, 1H), 8.04 (m, 1H).
LCMS Rt = 1.38 min, MS m / z 226 [MH] ⁺ .

Preparation Example 234
5-chloro-4-({5-chloro-6-[(1R) -2,2,2-trifluoro-1-methylethoxy] pyridin-3-yl} oxy) -2-methyl 4-fluorobenzoate Phenyl

5-chloro-6-[(1R) -2,2,2-trifluoro-1-methylethoxy] pyridin-3-ol (Preparation Example 235, 360 mg, 0.86 mmol) and 5-chloro-2,4- To a mixture of 4-methylphenyl difluorobenzoate (Preparation Example 12, 242 mg, 0.86 mmol) in DMSO (2 mL) was added K ₂ CO ₃ (237 mg, 1.7 mmol) in N ₂ at room temperature. The mixture was stirred for 5 hours. The reaction was quenched with water and extracted with DCM (3 × 5 mL). The mixture was filtered through a phase separation cartridge. The combined organic phases were washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by blowing N ₂ to give the crude product. The crude product was purified by silica gel column chromatography eluting with 0-40% EtOAc / heptane to give the title compound (429 mg, 99%) as a colorless gum.
¹ HNMR (400 MHz, CDCl ₃ ): δ 1.58 (m, 3H), 2.38 (s, 3H), 5.77 (m, 1H), 6.65 (d, 1H), 7.09 (m, 2H), 7.23 (m, 2H), 7.55 (d, 1H), 7.93 (d, 1H), 8.24 (d, 1H)
LCMS Rt = 3.64 min, MS m / z 504 [MH] ⁺ .

Preparation Example 235
5-Chloro-6-[(1R) -2,2,2-trifluoro-1-methylethoxy] pyridin-3-ol

3-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-[(1R) -2,2,2-trifluoro-1-methyl Ethoxy] pyridine (Preparation Example 236, 560 mg, 1.59 mmol) in acetone (5 mL) is added dropwise Oxone® aqueous solution (5 mL, 1.24 g, 1.91 mmol) with stirring at 0 ° C. for 15 minutes. did. The reaction mixture is diluted with water and extracted with EtOAc (3 × 15 mL) and the combined organic phases are washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product. The product was obtained as a brown oil. The crude product was purified by silica gel column chromatography eluting with 0-40% EtOAc / heptane to give the title compound (361 mg, 54%) as a yellow oil.
¹ HNMR (400 MHz, CDCl ₃ ): δ 2.07 (s, 3H), 5.18 (br s, 1H), 5.64 (m, 1H), 7.32 (d, 1H), 7.68 (d, 1H).
LCMS Rt = 2.24 min MS m / z 242 [MH] ⁺ , 240 [MH] ^- .

Preparation Example 236
3-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-[(1R) -2,2,2-trifluoro-1-methyl Ethoxy] pyridine

3-chloro-2-[(1R) -2,2,2-trifluoro-1-methylethoxy] pyridine (Preparation Example 237, 360 mg, 1.6 mmol), 4,4,4 ′, 4 ′, 5, 5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (486 mg, 1.92 mmol), di-μν-methanolatodiiridium (Ir-Ir) -cycloocta-1, A mixture of 5-diene (1: 2) (33 mg, 0.05 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridine (13 mg, 0.05 mmol) in TBME (8 mL) was microwaved. Heated at 80 ° C. for 30 minutes. The solvent was reduced by bubbling N ₂ and the residue was filtered through a silica gel pad eluting with EtOAc (50 mL). The filtrate was concentrated in vacuo to give the title compound. This material was used in the next step without further purification.
LCMS Rt = 3.46 min, MS m / z 352 [MH] ⁺ .

Preparation Example 237
3-Chloro-2-[(1R) -2,2,2-trifluoro-1-methylethoxy] pyridine

DMSO (7 mL) of 3-chloro-2-fluoropyridine (500 mg, 3.8 mmol) and (2R) -1,1,1-trifluoropropan-2-ol (75 wt% TBME solution, 752 mg, 4.9 mmol) To the solution, Cs ₂ CO ₃ (1.6 g, 4.9 mmol) was added in N ₂ at room temperature. The resulting mixture was stirred at 80 ° C. for 2 hours. To the reaction mixture, an additional 500 mg of (2R) -1,1,1-trifluoropropan-2-ol was added and the mixture was stirred at the same temperature for an additional 2.5 hours. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The organic phase was separated, washed with brine (2 × 30 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product as a colorless oil. The crude product was purified by silica gel column chromatography eluting with 0-30% EtOAc / heptane to give the title compound (365 mg, 43%) as a colorless oil.
¹ HNMR (400 MHz, CDCl ₃ ): δ 1.55 (m, 3H), 5.81 (m, 1H), 6.93 (m, 1H), 7.69 (m, 1H), 8.04 (m, 1H)
LCMS Rt = 2.70 min, MS m / z 226 [MH] ⁺ .

Preparation Example 238
2-Bromo-3-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine

(1,5-Cyclooctadiene) (methoxy) iridium (I) dimer (86 mg, 0.13 mmol) was converted to 2-bromo-3-chloropyridine (5.0 g, 26.0 mmol), 4,4 ′. -Di-tert-butyl-2,2'-dipyridyl (70 mg, 0.26 mmol) and bis (pinacolato) diboron (5.28 g, 20.8 mmol) in heptane (45 mL) degassed mixture and Heated at 90 ° C. for 18 hours. The cooled reaction was quenched with methanol (10.0 mL) and evaporated to give the title compound as a red oil that was used in the next step without further purification.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.14 (s, 12H), 7.84 (s, 1H), 8.32 (s, 1H)
LCMS Rt = 2.34 min, MS m / z 238 [MH] ⁺ .

Preparation Example 239
6-Bromo-5-chloropyridin-3-ol

Crude 2-bromo-3-chloro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (Preparation Example 238, 8.27 g, 26.0 mmol) To this was added methanol (100 mL) and the stirred solution was cooled in an ice bath. To this solution was added a hydrogen peroxide solution (35% aqueous solution, 4.25 mL, 43.8 mmol) over 5 minutes. The solution was allowed to warm slowly to room temperature for 18 hours. A 1M aqueous sodium thiosulfate solution (500 mL) was added while stirring at high speed for 15 minutes to deactivate the reaction system. The organics were removed in vacuo and brine (100 mL) was added. The aqueous phase was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were dried over magnesium sulfate, filtered and the solvent removed to give an off-white solid. This solid was triturated with 4: 1 heptene: ethyl acetate and filtered to give the title compound as a white solid (2.20 g, 41%).
LCMS Rt = 2.36 min, MS m / z 209 [MH] ^+
1 HNMR (400 MHz, CDCl ₃ ): δ 5.33 (br s, 1H), 7.32 (s, 1H), 7.98 (s, 1H).

Preparation Example 240
Methyl 5-chloro-2-fluoro-4-methylbenzoate

To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (10 g, 44.7 mmol) in methanol (200 mL) was added 1,1′-binaphthalene-2,2′-diylbis (diphenylphosphine) -dichloro. Palladium (1: 1) (358 mg, 0.447 mmol) and N, N-diethylethanamine (8.11 mL, 58.2 mmol) were added. The resulting mixture was placed in a bomb, pressurized to 80 psi with carbon monoxide, and heated at 80 ° C. for 18 hours. The cooled reaction mixture was then concentrated in vacuo to give a semi-solid that was dissolved in EtOAc (300 mL) and washed with water (200 mL). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil that solidified on standing (9.87 g). This solid was purified by silica gel column chromatography eluting with 0-20% EtOAc / heptane to give the title compound as a crystalline white solid (8.47 g, 93%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.40 (s, 3H), 3.92 (s, 3H), 7.03 (d, 1H), 7.91 (d, 1H)
LCMS Rt = 1.64 min, no molecular ions were observed.

Preparation Example 241
5-Chloro-2-fluoro-4-methylbenzoic acid

To a stirred solution of methyl 5-chloro-2-fluoro-4-methylbenzoate (Preparation Example 240, 340 mg, 1.68 mmol) in dioxane / water (5: 1, 12 mL) was added aqueous sodium hydroxide (5 M, 1.63 mL). , 8.39 mmol). The reaction mixture was stirred at room temperature for 18 hours and then evaporated in vacuo. The resulting residue was suspended in water and extracted with diethyl ether (3 × 20 mL). The aqueous layer was separated, cooled in an ice bath, acidified with aqueous hydrochloric acid (6M) and extracted with EtOAc (30 mL). The organic phase was washed with brine (2 × 20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound as a white solid (266 mg, 84%).
¹ H NMR (400 MHz, d ₆ -DMSO): δ 2.36 (s, 3H), 7.38 (dd, 1H), 7.80 (d, 1H).
LCMS Rt = 1.39 min, MS m / z 187 [MH] ^- .

Preparation Example 242
5-Chloro-2-fluoro-4-methyl-N- (methylsulfonyl) benzamide

To a solution of 5-chloro-2-fluoro-4-methylbenzoic acid (Preparation Example 241, 200 g, 1.06 mol) in DCM (1.4 L) was added methanesulfonamide (152 g, 1.6 mol), 4- (dimethylamino). ) Pyridine (183 g, 1.6 mol) and N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (306 g, 1.6 mol) were added. After allowing the reaction mixture to naturally heat at 30 ° C. over 30 minutes, it was stirred in a nitrogen atmosphere at room temperature for 18 hours. The reaction mixture was washed with aqueous hydrochloric acid (4M, 0.8 L). The organic layer was separated, washed with water (500 mL), dried over sodium sulfate, and concentrated in vacuo to give a tan solid that was recrystallized from hot EtOAc (0.9 L). , N-heptane (100 mL) was added and cooled to give the title compound (118 g, 45%):
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.42 (s, 3H), 3.42 (s, 3H), 7.10 (d, 1H), 8.05 (d, 1H), 8.78 (br, 1H).

Preparation Example 243
4- (Bromomethyl) -5-chloro-2-fluoro-N- (methylsulfonyl) benzamide

To a suspension of 5-chloro-2-fluoro-4-methyl-N- (methylsulfonyl) benzamide (Preparation Example 242, 118 g, 0.45 mol) in 1,2-dichloroethane (1.25 L) was added N-bromosuccinimide. (91 g, 0.51 mol) and benzoyl peroxide (5 g, 20 mmol) were added and the mixture was heated to reflux for 18 hours. N-bromosuccinimide (30 g, 0.17 mol) was then added and the solution was heated for an additional 24 hours. Further, a certain amount of N-bromosuccinimide (20 g, 0.11 mol) was added and the solution was heated for 3 hours, then cooled, with water (1 L) containing aqueous sodium thiosulfate solution (200 mL, 0.5 M). Washed. The organic layer was washed with water (500 mL), dried over sodium sulfate and concentrated in vacuo to give a crude solid. To this crude solid in EtOAc (1 L) was added diisopropylethylamine (130 mL, 0.75 mol) and diethyl phosphite (27.6 g, 0.2 mol) and the mixture was stirred in nitrogen for 5 hours, Washed with aqueous hydrochloric acid (1 L, 2M), dried over magnesium sulfate and evaporated to give a dark solid. Trituration with diethyl ether (200 mL) gave the first crop of the title compound as a tan solid (68 g). The filtrate was purified by silica gel chromatography eluting with 10% EtOAc / DCM (containing acetic acid (1%)) and then crystallized from acetonitrile (130 mL) to give the title compound as a second crop. (30 g):
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.41 (s, 3H), 4.54 (s, 2H), 7.38 (d, 1H), 8.14 (d, 1H), 8.78 (br, 1H).

Preparation Example 244
2,5-Difluoro-4-methyl-N- (methylsulfonyl) benzamide

2-5-Difluoro-4-methylbenzoic acid (6.0 g, 34.9 mmol), diisopropylethylamine (13.5 g, 105.0 mmol), propanephosphonic acid cyclic anhydride (50 mL, 50% w / w in EtOAc solution) , 84.0 mmol) and methanesulfonamide (6.6 g, 69.7 mmol) in THF (200 mL) was heated to reflux in a nitrogen atmosphere for 18 hours. After cooling, the solution was evaporated in vacuo and the resulting residue was suspended in water. The mixture was extracted with EtOAc (300 mL) and the organic extract was washed with brine (2 × 80 mL). The organic layer was dried over sodium sulfate and evaporated in vacuo to give a solid. This solid was triturated with hexanes to give the title compound (7.6 g, 87%) as an off-white solid.
¹ H NMR (400 MHz, d ₆ -DMSO): δ 2.26 (s, 3H), 3.34 (s, 3H), 7.33 (m, 1H), 7.44 (m, 1H).
LCMS Rt = 1.24 min, MS m / z 248 [MH] ^- .

Preparation Example 245
4- (Bromomethyl) -2,5-difluoro-N- (methylsulfonyl) benzamide

2,5-difluoro-4-methyl-N- (methylsulfonyl) benzamide (Preparation Example 244, 5.07 g, 20.3 mmol), N-bromosuccinimide (freshly recrystallized and dried 4.71 g, 26.4 mmol) and azobisisobutyronitrile (0.05 g, 0.30 mmol) in 1,2-dichloroethane (100 mL) was heated to reflux in nitrogen while irradiating with lamp light. After 2 hours, additional azobisisobutyronitrile (0.05 g, 0.30 mmol) was added and the reaction was heated at reflux for an additional 2 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. The resulting residue was partitioned between brine (200 mL) and EtOAc (2 × 150 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give a pale yellow oil that solidified on standing (7.88 g). This solid was purified by silica gel chromatography eluting with 0-30% EtOAc / heptane to give the title compound as a white solid (3.71 g, 56%):
¹ H NMR (400 MHz, d ₆ -DMSO): δ 3.34 (s, 3H), 4.69 (s, 2H), 7.58 (m, 2H).
LCMS Rt = 1.37 min, MS m / z 326 [MH] ^- .

Preparation Example 246
2-Bromo-3- (bromo-difluoro-methoxy) -pyridine

To a suspension of sodium hydride (1.72 g, 43.1 mmol) in NMP (50 mL) was added a solution of 2-bromo-3-hydroxypyridine (5 g, 28.74 mmol) in NMP (50 mL). The mixture was stirred at room temperature for 30 minutes, then heated at 50 ° C. for 45 minutes and then cooled to room temperature. Dibromodifluoromethane (3.15 mL, 34.5 mmol) was added slowly and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched slowly into saturated aqueous ammonium chloride (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with water (3 × 100 mL), brine (2 × 100 mL), dried over MgSO ₄ and concentrated in vacuo to give a brown gum. The residue was purified by silica gel column chromatography eluting with 70/30 heptane / EtOAc to give the title compound as a colorless oil (1.2 g, 14%).
¹ H NMR (400MHz, CDCl ₃ ): δ 7.35 (m, 1H), 7.65 (m, 1H), 8.40 (m, 1H)
LCMS Rt = 2.36 min MS m / z 303 [MH] ⁺ .

Preparation Example 247
2-Bromo-3-trifluoromethoxypyridine

To a cooled solution (−78 ° C.) of 2-bromo-3- (bromo-difluoro-methoxy) -pyridine (Preparation Example 246, 1 g, 3.3 mmol) in DCM (20 mL) (in a Teflon flask) was added tetra. Silver fluoroborate (1.41 g, 7.26 mmol) was added. The mixture was slowly warmed to room temperature and kept stirring for 18 hours. The reaction mixture was partitioned between saturated aqueous NaHCO ₃ (50 mL) and DCM (2 × 50 mL) (using a phase separation cartridge). The combined organic layers were evaporated to give the title compound as a colorless oil (635 mg, 80%).
¹ H NMR (CDCl ₃ , 400MHz): δ 7.45 (m, 1H), 7.70 (m, 1H), 8.55 (m, 1H)
LCMS Rt = 2.03 min MS m / z 241 [MH] ⁺ .

Preparation Example 248
2-Cyclopropyl-3- (trifluoromethoxy) pyridine

2-Bromo-3- (trifluoromethoxy) pyridine (Preparation 247, 776 mg, 3.21 mmol), cyclopropylboronic acid (331 mg, 3.85 mmol) and tribasic potassium phosphate (1.70 g, 8.02 mmol) Of toluene (10 mL) and water (3 mL) was degassed with nitrogen at 80 ° C. for 15 min. Palladium acetate (36 mg, 0.16 mmol) and tricyclohexylphosphine (90 mg, 0.32 mmol) were added and the reaction mixture was stirred vigorously at 95 ° C. for 18 hours under nitrogen. The solution was concentrated in vacuo, diluted with water (25 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with 10% diethyl ether / heptane to give the title compound as a colorless oil (292 mg, 45%).
¹ H NMR (400MHz, CDCl3): δ 1.03 (m, 2H), 1.12 (m, 2H), 2.37 (m, 1H), 7.06 (m, 1H), 7.46 (m, 1H), 8.36 (m, 1H )
LCMS Rt = 2.51 min, no MS ionization.

Preparation Example 249
1- (3-Chloropyridin-2-yl) cyclobutanecarboxylate tert-butyl

Prepared according to Preparation Example 229 using tert-butyl cyclobutylcarboxylate.
LCMS Rt = 2.75 min, MS m / z 268 [MH] ⁺ .
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.38 (s, 9H), 1.86 (m, 1H), 2.23 (m, 1H), 2.76 (m, 4H), 7.15 (m, 1H), 7.94 (m , 1H), 8.48 (m, 1H).

Preparation Example 250
3-chloro-2-cyclobutylpyridine

Prepared according to Preparation Example 228 using tert-butyl 1- (3-chloropyridin-2-yl) cyclobutanecarboxylate (Preparation Example 249).
LCMS Rt = 1.19 min, MS m / z 168 [MH] ⁺ .
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.92 (m, 1H), 2.08 (m, 1H), 2.40 (m, 4H), 4.02 (m, 1H), 7.07 (m, 1H), 7.60 (m , 1H), 8.49 (m, 1H).

Preparation Example 251
Tert-Butyl 2- (3-chloropyridin-2-yl) -2-methylpropanoate

Prepared according to Preparation 229 using tert-butyl isobutyrate.
LCMS Rt = 1.39 min, MS m / z 256 [MH] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 1.41 (s, 9H), 1.62 (s, 6H), 7.15 (m, 1H), 7.64 (m, 1H), 8.46 (m, 1H).

Preparation Example 252
3-Chloro-2-isopropylpyridine

Prepared according to Preparation Example 228 using tert-butyl 2- (3-chloropyridin-2-yl) -2-methylpropanoate (Preparation Example 251).
LCMS Rt = 2.24min, MS m / z 156 [MH] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 1.30 (d, 6H), 3.58 (m, 1H), 7.07 (m, 1H), 7.62 (m, 1H), 8.47 (m, 1H).

Preparation Example 253
2,3-dicyclopropylpyridine

Prepared according to Preparation 48 using cyclopropylboronic acid and 2-bromo-3-chloropyridine.
LCMS Rt = 0.84 min, MS m / z 160 [MH] ⁺ .

Preparation Example 254
5,6-dicyclopropylpyridin-3-ol

According to Preparation 69, 2,3-dicyclopropylpyridine (Preparation 253) was used under reflux and purified by silica gel column chromatography eluting with 50% ethyl acetate / heptane.
LCMS Rt = 0.91 min, MS m / z 176 [MH] ⁺ .

Preparation Example 255
3-Chloro-2- (1,1,1,3,3,3-hexafluoropropan-2-yloxy) -5-nitropyridine

A 60% sodium hydride mineral oil dispersion (450 mg, 11.25 mmol) was suspended in anhydrous tetrahydrofuran (10 mL). The suspension was cooled to 0 ° C. and 1,1,1,3,3,3-hexafluoropropan-2-ol (1.74 g, 10.35 mmol) was added over 15 minutes. The suspension was stirred for 30 minutes and 2,3-dichloro-5-nitropyridine (1.50 g, 7.77 mmol) was added in several portions. The reaction was stirred at room temperature overnight and then concentrated in vacuo. The crude residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2 × 25 mL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give the title compound as an orange oil (2.55 g, 100%).
LCMS rt = 3.48min, no MS ionization
¹ H NMR (400 MHz, CDCl ₃ ): δ 6.48 (m, 1H), 8.58 (m, 1H), 9.00 (m, 1H).

Preparation Example 256
5-chloro-6- (1,1,1,3,3,3-hexafluoropropan-2-yloxy) pyridin-3-amine

3-chloro-2- (1,1,1,3,3,3-hexafluoropropan-2-yloxy) -5-nitropyridine (Preparation Example 255, 2.55 g, 7.9 mmol), ammonium chloride (2 .50 g, 46.7 mmol) and iron powder (1.70 g, 30.4 mmol) were suspended in a mixture of ethanol (10 mL) and water (3 mL). The suspension was heated at reflux for 3 hours and then allowed to cool to room temperature. The reaction mixture was filtered through a Celite ™ pad and the pad was washed with ethanol. The filtrate was concentrated in vacuo and the crude residue was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2 × 25 mL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 50% diethyl ether / heptane to give the title compound as a pale yellow oil (2.0 g, 87%).
LCMS rt = 3.24min, MS m / z 295 [MH] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 3.60 (s, 2H), 6.30 (m, 1H), 7.15 (m, 1H), 7.50 (m, 1H).

Preparation Example 257
Tert-Butyl 4-bromobenzoate

To a tert-butanol (30 mL) solution was added 4-bromobenzoic acid (4.00 g, 19.9 mmol) and dimethylaminopyridine (0.24 g, 1.99 mmol). After 1 minute, di-tert-butyl carbonate (8.68 g, 218 mmol) was added and the reaction was heated to 45 ° C. for 18 hours. The reaction system was cooled to room temperature, quenched by addition of aqueous HCl (0.25 M), and extracted with ethyl acetate. The extract was purified by silica gel column chromatography eluting with a silica plug (ethyl acetate: heptane = 1: 2) then 20% DCM / cyclohexane to give the title compound as a colorless oil (0.59 g, 10%).
LCMS (4.5 min) Rt = 3.87 min, no mass ions were observed.
¹ H NMR (400 MHz, CDCl 3): δ 1.58 (s, 9H), 7.52 (d, 2H), 7.81 (d, 2H).

Preparation Example 258
4- (5-Chloro-6- (1,1,1,3,3,3-hexafluoropropan-2-yloxy) pyridin-3-ylamino) benzoate tert-butyl

Tert-Butyl 4-bromobenzoate (Preparation Example 257, 250 mg, 0.97 mmol), 5-chloro-6- (1,1,1,3,3,3-hexafluoropropan-2-yloxy) pyridine-3 To a degassed suspension of amine (Preparation 256, 430 mg, 1.46 mmol) and potassium carbonate (403 mg, 2.92 mmol) in a tert-butanol (10 mL) / water (0.2 mL) mixture, Pd (OAc) ₂ (1 mol%) and BrettPhos (3 mol%) were added. The mixture was heated at 110 ° C. for 18 hours. After 18 hours, a certain amount of Pd (OAc) ₂ (1 mol%) and BrettPhos (3 mol%) were further added, and the reaction system was heated at 110 ° C. for 24 hours. The reaction was cooled to room temperature, ethyl acetate (50 mL) and water (15 mL) were added, the phases were separated and the combined organics were evaporated. The crude product was purified by silica gel column chromatography eluting with DCM / heptane (10% -80%) to give the title compound as an oil (0.22 g, 48%).
LCMS (4.5 min) Rt = 4.13 min, m / z 471 M [H] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 1.50 (s, 9H), 7.05 (m, 3H), 7.80 (m, 2H), 7.90 (s, 1H), 8.05 (s, 1H).
¹⁹ F NMR (400 MHz, CDCl ₃ ): δ -72 (s, 6F).

Preparation Example 259
4- (5-Chloro-6- (1,1,1,3,3,3-hexafluoropropan-2-yloxy) pyridin-3-ylamino) benzoic acid

4- (5-Chloro-6- (1,1,1,3,3,3-hexafluoropropan-2-yloxy) pyridin-3-ylamino) benzoic acid tert-butyl (Preparation Example 258, 220 mg,. 47 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) at room temperature and the reaction was stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography eluting with acetonitrile: water (5:95 to 95: 5) to give the title compound as a pale yellow solid (116 mg, 60%).
LCMS (4.5 min) Rt = 3.41 min, m / z 415 M [H] ^+
1 HNMR (400 MHz, CDCl ₃ ): δ 7.00-7.10 (m, 3H), 7.80 (m, 2H), 7.90 (s, 1H), 8.05 (s, 1H), 8.90 (s, 1H).

Preparation Example 260
2- (2,2,3,3-tetrafluoropropoxy) -3- (trifluoromethyl) pyridine

Suspension of 2,2,3,3-tetrafluoropropan-1-ol (5.54 g, 41.31 mmol) in sodium hydride (2.20 g, 55.08 mmol, 60% mineral oil liquid) in tetrahydrofuran (50 mL) The reaction mixture was stirred at room temperature for 30 minutes. Then a solution of 2-chloro-3- (trifluoromethyl) pyridine (5.00 g, 27.54 mmol) in tetrahydrofuran (50 mL) was added and the mixture was heated at 40 ° C. for 18 hours. The reaction mixture was allowed to cool to room temperature and then slowly quenched with water. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate / heptane to give the title compound as an oil (3.10 g, 41%).
LCMS Rt = 2.53 min, m / z not detected
¹ HNMR (400 MHz, CDCl ₃ ): δ 4.82 (t, 2H), 6.17-5.87 (m, 1H), 7.10-7.07 (m, 1H), 7.92 (d, 1H), 8.33 (d, 1H).

Preparation Example 261
2- (2,2,3,3-tetrafluoropropoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3- (trifluoromethyl) Pyridine

2- (2,2,3,3-tetrafluoropropoxy) -3- (trifluoromethyl) pyridine (Preparation 260, 3.06 g, 11.04 mmol) and bis (pinacolato) diboron (2.52 g, 9. 94 mmol) was dissolved in dioxane (30 mL) and the reaction mixture was degassed. After the reaction system was heated at 90 ° C., bis (1,5-cyclooctadiene) di-μ-methoxydiiridium (I) (72.90 mg, 0.11 mmol) and then 4,4′-di-tert- Butyl-2,2′-dipyridyl (59.00 mg, 0.22 mmol) was added and the reaction mixture was heated for 18 hours. The reaction system was cooled to 0 ° C. (ice bath), then slowly deactivated with methanol, and the solvent was evaporated. The residue was diluted with ethyl acetate, filtered through a silica gel pad, and the filtrate was concentrated in vacuo to give the title compound (4.45 g, 100%).
LCMS Rt = 3.94 min, m / z 404 [MH] ^+
1 HNMR (400 MHz, CDCl ₃ ): δ 1.35 (s, 12H), 4.85 (t, 2H), 6.15-5.88 (m, 1H), 8.26 (s, 1H), 8.66 (s, 1H).

Preparation Example 262
6- (2,2,3,3-tetrafluoropropoxy) -5- (trifluoromethyl) pyridin-3-ol

Hydrogen peroxide (1.29 mL, 13.33 mmol, 35% solution) was added to 2- (2,2,3,3-tetrafluoropropoxy) -5- (4,4,5,5-tetramethyl-1, To a solution of 3,2-dioxaborolan-2-yl) -3- (trifluoromethyl) pyridine (Preparation Example 261, 4.45 g, 11.04 mmol) in methanol (50 mL) at 0 ° C. (ice bath), reaction The mixture was allowed to warm to room temperature. After 3 hours, the reaction system was quenched with 1M sodium thiosulfate solution, and methanol was removed in vacuo. The residue was partitioned between ethyl acetate and water, the organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 30% heptane / ethyl acetate to give the title compound as an oil (2.95 g, 91%).
LCMS Rt = 2.30min, m / z 292 [MH] ^-
1 HNMR (400 MHz, CDCl ₃ ): δ 4.73 (t, 2H), 5.35 (br s, 1H), 6.13-5.87 (m, 1H), 7.49 (d, 1H), 7.93 (d, 1H).

Preparation Example 263
5-chloro-4- (6- (2,2,3,3-tetrafluoropropoxy) -5- (trifluoromethyl) pyridin-3-yloxy) -2-fluorobenzoate 4-methylphenyl

6- (2,2,3,3-tetrafluoropropoxy) -5- (trifluoromethyl) pyridin-3-ol (300 mg, 1.02 mmol) was dissolved in dimethyl sulfoxide (5 mL), and then potassium carbonate ( 282 mg, 2.04 mmol) followed by p-tolyl 5-chloro-2,4-difluorobenzoate (290 mg, 1.02 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was then partitioned between ethyl acetate and water, the organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 30% ethyl acetate / heptane to give the title compound as a gum (483 mg, 85%).
LCMS Rt = 4.18 min, m / z not detected
¹ HNMR (400 MHz, CDCl ₃ ): δ 2.38 (s, 3H), 4.84 (t, 2H), 6.17-5.88 (m, 1H), 6.64 (d, 1H), 7.10 (d, 2H), 7.24 ( d, 2H), 7.73 (s, 1H), 8.19 (s, 1H), 8.25 (d, 1H).

Preparation Example 264
Tert-Butyl 5-chloro-4-[(5-chloro-6-cyclopropylpyridin-3-yl) oxy] -2-fluorobenzoate

To a solution of tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation Example 59, 35.7 g, 143.86 mmol) in DMSO (97.6 mL) was added 5-chloro-6-cyclopropylpyridin-3-ol. (Preparation Example 69, 24.4 g, 143.86 mmol) was added and stirred at room temperature until a solution was obtained. Potassium carbonate (49.7 g, 359.65 mmol) was added in several portions while maintaining the internal temperature at 15-25 ° C. with a cold water jacket. The reaction mixture was stirred at room temperature for 12 hours, charged with cold water, and the resulting slurry was stirred for 90 minutes. The mixture was filtered, washed with water and dried to give the title compound as a pale yellow solid (54.0 g, 94%).
HPLC Rt = 8.593 min.

Preparation Example 265
5-Chloro-4-[(5-chloro-6-cyclopropylpyridin-3-yl) oxy] -2-fluorobenzoic acid

Dichloromethane (270 mL) of tert-butyl 5-chloro-4-[(5-chloro-6-cyclopropylpyridin-3-yl) oxy] -2-fluorobenzoate (Preparation 264, 54.0 g, 135.59 mmol) ) To the solution was added trifluoroacetic acid (30.76 mL, 406.77 mmol). The resulting solution was heated at 45 ° C. for 24 hours and concentrated under reduced pressure at 45 ° C. To the residue was added tert-butyl methyl ether (100 mL) and the resulting slurry was stirred at room temperature for 2.5 hours, filtered, washed with tert-butyl methyl ether (20 mL) and dried to give the title compound. Was obtained as an off-white solid (45.0 g, 97%).
¹ H NMR (400 MHz, CD ₃ OD): δ 1.02-1.09 (m, 4 H), 2.48-2.58 (m, 1H), 6.86 (d, 1H), 7.58 (d, 1H), 8.07 (d, 1H), 8.18 (d, 1H)
HPLC Rt = 6.485 min.

Preparation Example 266
2-Bromo-3- (1,1-difluoroethoxy) pyridine

A solution of 3-acetyl-2-bromopyridine (1.05 g, 5.25 mmol) in DCM (20 mL) was placed in a plastic bottle with xenon difluoride (1.78 g, 10.5 mmol) and HF / pyridine ( 14 mL, 160 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (200 mL) and quenched by slow addition to saturated aqueous NaHCO ₃ (200 mL) containing excess solid NaHCO ₃ (10 g). The layers were separated and the aqueous layer was further extracted with DCM (2 × 100 mL). The organics were dried over MgSO ₄ , filtered, concentrated in vacuo and azeotroped with toluene to remove pyridine. The crude product was dry loaded onto silica and purified by silica gel column chromatography eluting with heptane: EtOAc with a gradient of 95: 5-70: 30 to give the title compound as a colorless oil (700 mg). .
¹ HNMR (400 MHz, CDCl ₃ ): δ 2.03 (t, 3H), 7.26 (dd, 1H), 7.64 (m, 1H), 8.24 (dd, 1H).
LCMS Rt = 2.14 min, MS m / z 238 [MH] ⁺ .

Preparation Example 267
2-Cyclopropyl-3- (1,1-difluoroethoxy) pyridine

2-Bromo-3- (1,1-difluoroethoxy) pyridine (Preparation 266, 700 mg, 2.948 mmol), cyclopropylboronic acid (252 mg, 2.94 mmol), and potassium triphosphate (1.56 g, 7.35 mmol) was suspended in a mixture of toluene (100 mL) and water (20 mL) with rapid stirring. The suspension was heated to 80 ° C. and N ₂ gas was bubbled directly through the suspension for 30 minutes to degas the solvent. Next, the reaction system was heated to 95 ° C., tricyclohexylphosphine (82 mg, 0.29 mmol) was added, and then palladium acetate (33 mg, 0.15 mmol) was quickly added. The reaction was kept stirring and heated at 95 ° C. for 18 hours. The reaction was cooled to room temperature, filtered through an arbocel plug and eluted with ethyl acetate. The solvent was removed to give a dark yellow oil. Ethyl acetate (100 mL) was added and the organic phase was extracted with 2M HCl solution (3 × 100 mL). The organic phase was discarded. Ethyl acetate (150 mL) was added to the combined aqueous layers and solid sodium bicarbonate was added until the aqueous layer was pH 7. The mixture was transferred to a separatory funnel, the organic layer was removed and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic phases were dried over magnesium sulfate, filtered and the solvent removed to give a yellow oil. This material was purified by silica gel column chromatography eluting with 1: 1 heptane: ethyl acetate to give the title compound as a colorless oil (252 mg, 43%).
LCMS (5.0 min) Rt = 3.13 min, m / z 200 [MH] ^+
1 HNMR (400 MHz, CDCl ₃ ): δ 0.92-0.99 (m, 2H), 1.03-1.10 (m, 2H), 1.97 (t, 3H), 2.30-2.38 (m, 1H), 7.01 (m, 1H ), 7.45 (d, 1H), 8.28 (d, 1H).
¹⁹ FNMR (400 MHz, CDCl ₃ ): δ -64 (s, 2F).

Preparation Example 268
2-Cyclopropyl-3- (1,1-difluoroethoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine

To dioxane (10 mL) was added 2-cyclopropyl-3- (1,1-difluoroethoxy) pyridine (Preparation 267, 252 mg, 1.27 mmol) and bis (pinacolato) diboron (289 mg, 1.14 mmol). The solution was degassed by bubbling N ₂ for 30 minutes. The solution was heated to 80 ° C. and 4,4-di-tert-butyl-2,2-dipyridyl (6.80 mg, 0.03 mmol) and cyclooctadiene (dimethoxy) iridium (I) dimer (8. 30 mg, 0.01 mmol) was added. The flask was degassed with N ₂ and left at 80 ° C. for 18 hours. The reaction was cooled in an ice bath, quenched by slow addition of methanol (20 mL) and concentrated in vacuo to give the title compound as a reddish brown oil that was used crude (412 mg, theoretical 1 .27 mmol).
LCMS (5.0 min) Rt = 1.92 min
¹ HNMR (400 MHz, CDCl ₃ ): δ 0.95-1.12 (m, 4H), 1.32 (s, 12H), 1.98 (t, 3H), 2.30-2.40 (m, 1H), 7.79 (s, 1H), 8.60 (s, 1H).

Preparation Example 269
6-Cyclopropyl-5- (1,1-difluoroethoxy) pyridin-3-ol

Crude 2-cyclopropyl-3- (1,1-difluoroethoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (Preparation Example 268) (412 mg, 1.27 mmol) was added methanol (20 mL) and the stirred solution was cooled in an ice bath. To this solution was added a hydrogen peroxide solution (35% aqueous solution) (0.15 mL, 1.52 mmol) over 2 minutes. The solution was allowed to warm slowly to room temperature over 18 hours. 1M aqueous sodium thiosulfate solution (50 mL) was added to quench the reaction and stirred rapidly for 15 minutes. The organics were removed in vacuo and brine (50 mL) was added. The aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organics were dried over magnesium sulfate, filtered and the solvent removed to give an orange oil. The oil was purified on a silica plug eluting with 1: 1 ethyl acetate: heptane to give the title compound as a white solid (155 mg, 57%).
LCMS (5.0 min) Rt = 2.08 min, m / z 216 M [H] ^+
1 HNMR (400 MHz, CDCl ₃ ): δ 0.88-0.99 (m, 4H), 1.95 (t, 3H), 2.16-2.25 (m, 1H), 7.14 (s, 1H), 7.87 (s, 1H).

Preparation Example 270
Tert-Butyl 5-chloro-4- (6-cyclopropyl-5- (1,1-difluoroethoxy) pyridin-3-yloxy) -2-fluorobenzoate

6-cyclopropyl-5- (1,1-difluoroethoxy) pyridin-3-ol (Preparation Example 269, 155 mg, 0.72 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (179 mg, 0 .72 mmol) and potassium carbonate (299 mg, 2.16 mmol) in dimethyl sulfoxide (3 mL) were stirred at room temperature for 4 hours. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with 5% diethyl ether / heptane to give the title compound as a white solid (260 mg, 81%).
LCMS Rt = 4.23 min
MS m / z 444 [MH] ^+
1 H NMR (400MHz, CD ₃ OD): δ 1.02 (m, 4H), 1.58 (s, 9H), 2.02 (m, 3H), 2.39 (m, 1H), 6.80 (m, 1H), 7.35 (m , 1H), 7.98 (m, 1H), 8.12 (m, 1H).

Preparation Example 271
5-Chloro-4- (6-cyclopropyl-5- (1,1-difluoroethoxy) pyridin-3-yloxy) -2-fluorobenzoic acid

Dichloromethane of 5-chloro-4- (6-cyclopropyl-5- (1,1-difluoroethoxy) pyridin-3-yloxy) -2-fluorobenzoate (Preparation 270, 260 mg, 0.59 mmol) To the (5 mL) solution, trifluoroacetic acid (440 μL, 5.86 mmol) was added. The reaction mixture was stirred at room temperature for 48 hours then concentrated in vacuo and the crude residue was azeotroped with methanol (2 × 25 mL). The crude material was purified by silica gel column chromatography eluting with 50% ethyl acetate / heptane to give the title compound as a white solid (200 mg, 96%).
LCMS Rt = 2.67 min, MS m / z 388 [MH] ^+
1 H NMR (400MHz, CDCl ₃ ): δ 1.03 (m, 2H), 1.12 (m, 2H), 2.01 (m, 3H), 2.35 (m, 1H), 6.59 (m, 1H), 7.33 (m, 1H), 8.14 (m, 1H), 8.21 (m, 1H), 10.44 (s, 1H).

  The following compounds were prepared by methods analogous to those described for Preparation Example 22.

  The following compounds were prepared by methods analogous to those described for Preparation Example 23.

  The following compounds were prepared by methods analogous to those described for Preparative Example 58 (in the case of Preparative Examples 290 and 291, a method similar to that described for Preparative Example 14 is performed first).

  The following compounds were prepared by methods analogous to those described for Preparation Example 14.

  The following compounds were prepared by methods analogous to those described for Preparation Example 9.

Preparation Example 298
5-chloro-4-((5-chloro-6-((1,1,1-trifluoropropan-2-yl) oxy) pyridin-3-yl) oxy) -2-fluorobenzoic acid (S)- tert-butyl

Tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation Example 59, 8.3 g, 33.4 mmol) was added to 5-chloro-6-[(1S) -2,2,2-trifluoro-1 -Methylethoxy] pyridin-3-ol (Preparation Example 231, 16.2 g, 66.8 mmol) and potassium carbonate (27.8 g, 200 mmol) were added to a solution of dimethyl sulfoxide (100 mL). The reaction mixture was stirred at room temperature for 18 hours and then quenched with aqueous sodium hydroxide (1M, 100 mL). A white precipitate formed and was collected by filtration to give the title compound as a white solid (9.2 g).
LCMS Rt = 3.43min, m / z 468 [MH] ^-
1 H NMR (400 MHz, CDCl ₃ ): δ 1.55 (d, 3H), 1.59 (s, 9H), 5.73 (m, 1H), 6.58 (d, 1H), 7.47 (d, 1H), 7.86 (d , 1H), 7.99 (d, 1H).
¹⁹ F NMR (400 MHz, CDCl ₃ ): δ -79, -108.

Preparation Example 299
(S) -5-Chloro-4-((5-chloro-6-((1,1,1-trifluoropropan-2-yl) oxy) pyridin-3-yl) oxy) -2-fluorobenzoic acid

Trifluoroacetic acid (4.4 mL, 58.7 mmol) was added to 5-chloro-4-((5-chloro-6-((1,1,1-trifluoropropan-2-yl) oxy) pyridine-3- Yl) oxy) -2-fluorobenzoic acid (S) -tert-butyl (Preparation 298, 9.2 g, 19.6 mmol) was added to a solution of dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 20 hours and then concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with heptane: ethyl acetate (95: 5 to 40:60) to give the title compound as a white solid (6.9 g, 85%).
LCMS Rt = 2.88min, m / z 414 [M + H] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 1.56 (d, 3H), 5.75 (m, 1H), 6.60 (d, 1H), 7.52 (d, 1H), 7.90 (d, 1H), 8.15 (d , 1H).
¹⁹ F NMR (400 MHz, CDCl ₃ ): δ -79, -105.
The ability of compounds of formula (I) to block the Nav1.7 (or SCN9A) channel was measured using the assay described below.

Cell Line Construction and Maintenance Human embryonic kidney (HEK) cells were transfected with hSCN9A construct using Lipofectamine reagent (Invitrogen) using standard techniques. Cells stably expressing the hSCN9A construct were identified by resistance to G-418 (400 μg / ml). Clones were screened for expression using the whole cell voltage clamp method.

Cell culture HEK cells stably transfected with hSCN9A were supplemented with 10% heat-inactivated fetal bovine serum and 400 μg / ml G-418 in a 37 ° C. incubator with 10% CO _{2 in} a humidified atmosphere. Maintained in DMEM medium. For HTS, cells are harvested from the flask by trypsinization and re-plated into a suitable multiwell plate (typically 96 or 384 well / plate) so that it is confluent within 24 hours of plating. Cultured. For electrophysiological studies, cells were removed from the culture flasks by brief trypsinization and re-plated at low density on coverslips. Typically, cells within 24-72 hours after plating were used for electrophysiological experiments.

Electrophysiological recording A cover glass containing HEK cells expressing hSCN9A is placed in a bath on the stage of an inverted microscope and has the following composition: 138 mM NaCI, 2 mM CaCI ₂ , 5.4 mM KCI, 1 mM was perfused with extracellular solution of MgCl _2, 10mM glucose and 10mM of HEPES (adjusted to pH7.4 with NaOH) (about 1 ml / min). Pipettes were filled with an intracellular solution of the following composition: 135 mM CsF, 5 mM CsCl, 2 mM MgCl ₂ , 10 mM EGTA, 10 mM HEPES (adjusted to pH 7.3 with NaOH). This had a resistance of 1-2 megohms. The osmolarity of the extracellular and intracellular solutions was 300 mOsm / kg and 295 mOsm / kg, respectively. All recordings were performed at room temperature (22-24 ° C.) using an AXOPATCH 200B amplifier and PCLAMP software (Axon Instruments, Burlingame, Calif.).

  The hSCN9A current in HEK cells was measured using the whole cell configuration of the patch clamp method (Hamill et al., 1981). Uncompensated series resistance was typically 2-5 megohms, and over 85% series resistance compensation was achieved as usual. As a result, the voltage error was negligible and no correction was made. Current records were obtained at 20-50 kHz and filtered at 5-10 kHz.

HEK cells stably transfected with hSCN9A are observed with Hoffman contrast optics and placed in front of an array of outflow tubes that release extracellular solution containing either control or compound. It was. All compounds were dissolved in dimethyl sulfoxide to prepare a 10 mM stock solution that was then diluted in extracellular solution to achieve the desired final concentration. The final concentration of dimethyl sulfoxide (less than 0.3% dimethyl sulfoxide) was found to have no significant effect on hSCN9A sodium current. The voltage dependence of inactivation was measured by applying a series of pre-depolarization pulses (length 8 seconds, increment 10 mV) from a negative holding potential. The voltage was then immediately stepped to 0 mV to assess the magnitude of the sodium current. The current induced at 0 mV was plotted as a function of the prepulse potential to allow estimation of the voltage at which 50% of the channel was inactivated (midpoint of inactivation or V1 / 2). Inhibit the hSCN9A sodium channel by activating the channel with a 20 millisecond voltage step to 0 mV, then an 8 second conditioning prepulse to V1 / 2 determined empirically Compounds were tested for potency. The effect (inhibition rate (%)) of the compound was measured by the difference in current amplitude before and after the addition of the test compound. For ease of comparison, an “estimated IC-50” (EIC) from a single electrophysiological data point is given by the following formula (test concentration, uM) × (100−inhibition rate (%) / inhibition rate (%)) ₅₀ ) The value was calculated. Inhibition values below 20% and above 80% were excluded from the calculation.

Electrophysiological assays were performed using PatchXpress 7000 hardware and associated software (Molecular Devices). All assay buffers and solutions were the same as those used in the conventional whole cell voltage clamp experiments described above. hSCN9A cells were grown to 50% -80% confluence as described above and harvested by trypsinization. Trypsinized cells were washed and resuspended in extracellular buffer at a concentration of 1 × 10 ⁶ cells / ml. The liquid handling function implemented in PatchXpress was used to dispense cells and add test compounds. Measurement of the voltage midpoint of inactivation was as described for conventional whole cell recording. The cells were then voltage clamped to V1 / 2 determined empirically and the current was activated by a 20 millisecond voltage step up to 0 mV.

Electrophysiological assays were also performed using an Ionworks Quattro automated electrophysiological measuring device (Molecular Devices). Intracellular and extracellular solutions were as described above except that 120 μg / ml amphotericin was added to the intracellular solution to perforate the membrane and allow electrical access to the cells. Similarly for PatchXpress, hSCN9A cells were grown and harvested, and the cells were resuspended in extracellular solution at a concentration of 1 × 10 ⁶ cells / ml. The liquid handling function implemented in Ionworks Quattro was used to dispense cells and add test compounds. Then a voltage step to completely inactivate the sodium channel, followed by a short hyperpolarization recovery period that allows partial recovery from inactivation due to unblocked sodium channels A voltage procedure consisting of a test depolarization voltage step to evaluate the magnitude of inhibition by the test compound was applied. The effect of the compound was measured based on the current amplitude difference between the scan before compound addition and the scan after compound addition.

The compounds of the examples were tested in the above assay and found to have an EIC ₅₀ (μM) value of Nav1.7 as specified in the table below. All data was obtained from the PatchXpress assay unless otherwise stated explicitly.

Similar to that described above, but using an assay in which the SCN9A gene is replaced with the SCN5A gene, the ability of compounds of formula (I) to block the Nav1.5 (or SCN5A) channel can also be measured. . All other conditions are the same, including the same cell line and cell growth conditions. Estimated IC ₅₀ is measured with semi-inactivation against Nav1.5. These results can be compared to EIC ₅₀ values in the Nav1.7 channel to determine the selectivity of a given compound over Nav1.7 versus Nav1.5.

Claims (23)

Compound of formula (I):

Or a pharmaceutically acceptable salt thereof, wherein
X is O, S, NH or CH ₂ ;
Het ¹ is (i) 9-membered or 10-membered heteroaryl containing 1 to 3 nitrogen atoms, or (ii) ¹ to 3 heteroaryls independently selected from Y ¹ and Y ² A 6-membered, 9-membered or 10-membered heteroaryl containing 1 to 3 nitrogen atoms, substituted with a substituent,
Y ¹ and Y ² are independently optionally substituted with F, Cl, CN, NO ₂ , (C ₃ -C ₈ ) cycloalkyl and / or 1 to 8 Fs in the range allowed by the valence (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl optionally substituted with 1 to 8 Fs in the range allowed by valence, NR ⁷ R ⁸ , optionally independently 1 to 3 R ⁹ or (C ₁ -C ₈ ) alkyloxy substituted with 1-8 F in the range allowed by the valence, optionally substituted with 1-8 F in the range allowed by the valence (C _3- C ₈₎ cycloalkyloxy, optionally phenyl substituted with 1-3 ^{R 10} independently substituted with 1-3 ^{R 10} optionally independently ^phenoxy, Het 2, Het ² - oxy and Het ³ wherein (C ₃ -C ₈ ) cycloalkyloxy is , Optionally fused to a phenyl ring, or independently substituted with 1 to 3 R ¹⁰ ,
R ¹ is (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, each of which is optionally substituted with 1 to 8 Fs in the range allowed by the valence;
R ² , R ³ , R ⁴ are independently H, F, Cl or —OCH ₃ ;
R ⁵ is H, CN, F, Cl or R ⁶
R ⁶ is a group selected from (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkyloxy, wherein each group is 1-8 Fs in the range allowed by the valence Is optionally substituted,
R ⁷ and R ⁸ are independently H, optionally independently (C ₁ -C ₈ ) alkyl optionally substituted with 1 to 3 R ¹¹ , optionally with ₁ to ₈ Fs in the range allowed by the valence. Substituted (C ₃ -C ₈ ) cycloalkyl, “C-linked” Het ² or “C-linked” Het ³ , wherein (C ₃ -C ₈ ) cycloalkyl is optionally fused to a phenyl ring. Or may be substituted with 1 to 8 F and / or 1 to 3 R ¹⁰ independently in the range allowed by the valence, or R ⁷ and R ⁸ may be bonded together. Together with the nitrogen atom forming a saturated bridged 7-9 membered ring,
R ⁹ is (C ₁ -C ₆ ) alkyloxy, (C ₃ -C ₈ ) cycloalkyl, Het ² , or optionally substituted with _{1 to} 3 F or (C ₁ -C ₆ ) alkyl. Independently phenyl substituted with 1 to 3 R ⁶ ,
R ¹⁰ is Cl, CN or R ⁶
R ¹¹ is F, (C ₁ -C ₆ ) alkyloxy, (C ₃ -C ₈ ) cycloalkyl optionally substituted with 1 to 3 F, “C-linked” Het ² , or optionally independently 1 to 3 phenyl substituted with R ⁶ ;
Het ² is a 3-8 membered saturated monoheterocycloalkyl containing 1 or 2 ring members selected from —NR ¹² — and —O—, wherein the monoheterocycloalkyl is a ring carbon atom _{1 to 1} independently selected from F, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkyloxy, (C ₀ -C ₄ ) alkylene and (C ₃ -C ₈ ) cycloalkyl Optionally substituted with 3 substituents,
Het ³ is a 5- or 6-membered heteroaryl containing 1 to 3 nitrogen atoms, the heteroaryl being 1 to 3 substituents selected from F, Cl, CN and R ⁶ And R ¹² is H, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, wherein (C ₁ -C ₆ ) alkyl and (C ₃ -C ₈ ) cycloalkyl is optionally substituted with 1 to 3 F or absent when Het ² is “N-linked”). Het ¹ is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, and the heteroaryl is independently substituted with 1 to 3 substituents selected from Y ¹ and Y ² . The compound of claim 1. Het ¹ is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, which heteroaryl is independently substituted with 1 or 2 substituents selected from Y ¹ and Y ² The compound according to claim 1 or 2. The compound according to any one of claims 1 to 3, wherein Het ¹ is pyridyl or pyrimidinyl, each of which is independently substituted with one or two substituents selected from Y ¹ and Y ² . The compound according to any one of claims 1 to 4, wherein Het ¹ is pyridyl substituted with one or two substituents independently selected from Y ¹ and Y ² . Het ¹ is pyridyl substituted with one or two substituents independently selected from Y ¹ and Y ² and the pyridyl is oriented as follows: Compound described in 1.

When the pyridyl is 2-substituted with Y ¹ or 3-substituted with Y ² and is 2-substituted, it is 2-substituted with Y ¹ and 3-substituted with Y ² ; 7. A compound according to claim 6. Y ¹ is (C ₃ -C ₈ ) cycloalkyl and / or (C ₁ -C ₈ ) alkyl optionally substituted with ₁ to ₈ Fs in the range allowed by the valence, 1 in the range allowed by the valence. (C ₃ -C ₈ ) cycloalkyl optionally substituted with ˜8 F, (C ₁ -C ₆ ) alkyloxy optionally substituted with 1-8 F in the range allowed by the valence, ( C ₃ -C ₈₎ cycloalkyloxy, or Het ^2, a compound according to any one of claims 1 to 7. Y ² is F, Cl, CN, (C ₃ -C ₈ ) cycloalkyl and / or (C ₁ -C ₈ ) alkyl, optionally substituted with ₁ to ₈ F in the range allowed by the valence (C ₃ -C ₈ ) cycloalkyl optionally substituted with 1 to 8 Fs in the range allowed by the valence, optionally substituted with 1 to 8 Fs in the range allowed by the valence (C ₁ -C _{6) alkyloxy, (C} 3 -C ₈₎ cycloalkyloxy, or Het ^2, a compound according to any one of claims 1 to 8. R ¹ is _(C 1 _{~C 4)} alkyl or _(C 3 _{~C 6)} cycloalkyl, A compound according to any one of claims 1 to 9. The compound according to any one of claims 1 to 10, wherein R ¹ is methyl or cyclopropyl. R ^{2, R 3} and ^{R 4} are independently H, F or Cl, A compound according to any one of claims 1 to 11. R ⁵ is H, CN, F, Cl, (C ₁ -C ₄ ) alkyl optionally substituted with 1-8 F in the range allowed by the valence, or 1-8 in the range allowed by the valence. of an optionally substituted _(C 1 _{~C 4)} alkyloxy in F, a compound according to any one of claims 1 to 12. 14. The method according to claim 1, wherein R ⁵ is H, CN, F, Cl, CH ₃ , C ₂ H ₅ , CF ₃ , —OCH ₃ , —OC ₂ H ₅ or —OCF ₃ . Compound.   The compound according to claim 1, wherein X is O. A compound according to claim 1, wherein
X is O,
Het ¹ is (i) 9-membered or 10-membered heteroaryl containing 1 to 3 nitrogen atoms, or (ii) ¹ to 3 heteroaryls independently selected from Y ¹ and Y ² A 6-membered, 9-membered or 10-membered heteroaryl containing 1 to 3 nitrogen atoms, substituted with a substituent,
Y ¹ and Y ² are independently F, Cl, CN, (C ₃ -C ₈ ) cycloalkyl or (C ₁ -C ₈ ) alkyl optionally substituted with 1 to 3 F, 1 to 3 (C ₃ -C ₈ ) cycloalkyl optionally substituted with F, NR ⁷ R ⁸ , (C ₁ -C ₈ ) alkyloxy optionally substituted with 1 to 3 R ⁹ , (C ₃ -C ₈ ) cycloalkyloxy, optionally independently selected from 1 to 3 R ¹⁰ -substituted phenyl, Het ² and Het ³ , wherein (C ₃ -C ₈ ) cycloalkyloxy is Optionally fused to a phenyl ring, or independently substituted with 1 to 3 R ¹⁰ ,
R ¹ is (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, each of which is optionally substituted with 1 to 3 F;
R ² , R ³ , R ⁴ are independently H, F, Cl or —OCH ₃ ;
R ⁵ is H, CN, F, Cl or R ⁶
R ⁶ is a group selected from (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) alkyloxy, wherein each group is 1-5 F in the range allowed by the valence Is optionally substituted,
R ⁷ and R ⁸ are independently H, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl or “C-linked” Het, optionally independently substituted with 1 to 3 R ^{11. 2,} where, _(C 3 ~C ₈₎ cycloalkyl may be fused to an optionally phenyl ring, or independently may be substituted with 1-3 R ^10, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a saturated bridged 7-9 membered ring;
R ⁹ is F, (C ₁ -C ₆ ) alkyloxy, (C ₃ -C ₈ ) cycloalkyl optionally substituted with 1 to 3 F, Het ² , or optionally independently 1 to 3 R ⁶ substituted with R ⁶ of
R ¹⁰ is F, Cl or R ⁶ ;
R ¹¹ is F, (C ₁ -C ₆ ) alkyloxy, (C ₃ -C ₈ ) cycloalkyl optionally substituted with 1 to 3 F, “C-linked” Het ² , or optionally independently 1 to 3 phenyl substituted with R ⁶ ;
Het ² is a 3-8 membered saturated monoheterocycloalkyl containing 1 or 2 ring members selected from —NR ¹² — and —O—, wherein the monoheterocycloalkyl is a ring carbon atom _{1 to 1} independently selected from F, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkyloxy, (C ₀ -C ₄ ) alkylene and (C ₃ -C ₈ ) cycloalkyl Optionally substituted with 3 substituents,
Het ³ is a 5- or 6-membered heteroaryl containing 1 to 3 nitrogen atoms, the heteroaryl being 1 to 3 substituents selected from F, Cl, CN and R ⁶ And R ¹² is H, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, wherein (C ₁ -C ₆ ) alkyl and (C ₃ -C ₈ ) cycloalkyl is optionally substituted with 1 to 3 F or absent when Het ² is “N-linked”).   A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1-16 or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients.   17. A pharmaceutical composition according to claim 16 comprising one or more additional therapeutic agents.   A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 16, for use as a medicament.   17. A compound of formula (I) as defined in any of claims 1 to 16, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder in which a Nav1.7 inhibitor is required.   21. A compound for use according to claim 20, wherein the disorder for which a Nav1.7 inhibitor is required is pain, preferably neuropathic pain, nociceptive pain or inflammatory pain.   17. A compound of formula (I) as defined in any of claims 1-16 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disorder in which a Nav1.7 inhibitor is required. Use of.   Administration of a therapeutically effective amount of a compound of formula (I) as defined in any of claims 1 to 16, or a pharmaceutically acceptable salt thereof, to a human or animal in need of a Nav1.7 inhibitor A method of treating a disorder in said human or animal.